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Fats & FakesTowards improved control of malariaVisser, B.J.

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Citation for published version (APA):Visser, B. J. (2017). Fats & Fakes: Towards improved control of malaria.

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“The proportion of clay particles in the topsoil (i.e. mineral matter less than 0.002 mm in diameter).These tiny particles require microscopes to see them. The soil feels smooth when rubbed betweenone’s fingers. Clay-rich soils tend to contain more nutrients and because of their very high surfacearea can retain large amounts of moisture. As a result, they are favoured for agriculture. However,they can be difficult to cultivate when wet as they become very heavy and slow to drain. Can becomevery hard when dry. High clay content is generally indicative of the chemical weathering (andassociated transport) of parent material.” Adapted from: Soil Atlas of Africa, 2013. EuropeanCommission, Publications Office of the European Union, Luxembourg.1

115

Chapter 5

The influence of pregnancy on the pharmacokinetic propertiesof artemisinin combination therapy (ACT): a systematic review

Renée J. Burger

Benjamin J. Visser

Martin P. Grobusch

Michèle van Vugt

Malaria Journal 2016 Feb 18;15(1):99

Appendices and supplementary material are available online at:http://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1160-6



114

“The proportion of clay particles in the topsoil (i.e. mineral matter less than 0.002 mm in diameter).These tiny particles require microscopes to see them. The soil feels smooth when rubbed betweenone’s fingers. Clay-rich soils tend to contain more nutrients and because of their very high surfacearea can retain large amounts of moisture. As a result, they are favoured for agriculture. However,they can be difficult to cultivate when wet as they become very heavy and slow to drain. Can becomevery hard when dry. High clay content is generally indicative of the chemical weathering (andassociated transport) of parent material.” Adapted from: Soil Atlas of Africa, 2013. EuropeanCommission, Publications Office of the European Union, Luxembourg.1

115

Chapter 5

The influence of pregnancy on the pharmacokinetic propertiesof artemisinin combination therapy (ACT): a systematic review

Renée J. Burger

Benjamin J. Visser

Martin P. Grobusch

Michèle van Vugt

Malaria Journal 2016 Feb 18;15(1):99

Appendices and supplementary material are available online at:http://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1160-6



Chapter 5

116

Abstract

Background

Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs,including the different components of artemisinin-based combination therapy (ACT).However, small sample sizes make it difficult to draw strong conclusions based on individualpharmacokinetic studies. The aim of this review is to summarize the evidence of theinfluence of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations.

MethodsA PROSPERO-registered systematic review to identify clinical trials that investigated theinfluence of pregnancy on the pharmacokinetic properties of different forms of ACT wasconducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed,Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, BiosisPreviews and the African Index Medicus were searched for studies published up toNovember 2015. The following components of ACT that are currently recommend by theWorld Health Organization as first-line treatment of malaria in pregnancy were reviewed:artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine,sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil.

ResultsThe literature search identified 121 reports, 27 original studies were included. 829 pregnantwomen were included in the analysis. Comparison of the available studies showed lowermaximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the activemetabolite of all artemisinin derivatives, after oral administration of artemether, artesunateand dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seenin lumefantrine studies, indicating a low exposure and possibly reduced efficacy. Theinfluence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant.Sulfadoxine plasma concentration was significantly reduced and clearance rates were higherin pregnancy, while pyrimethamine and mefloquine need more research as no generalconclusion can be drawn based on the available evidence. For atovaquone, the available datashowed a lower maximum concentration and exposure. Finally, the maximum concentrationof cycloguanil, the active metabolite of proguanil, was significantly lower, possiblycompromising the efficacy.

The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review

117

ConclusionThese findings suggest that reassessment of the dose of the artemisinin derivate and somecomponents of ACT are necessary to ensure the highest possible efficacy of malariatreatment in pregnant women. However, for most components of ACT, data were insufficientand extensive research with larger sample sizes will be necessary to identify the exactinfluences of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations. In addition, different clinical studies used diverse study designs with variousreported relevant outcomes. Future pharmacokinetic studies could benefit from moreuniform designs, in order to increase quality, robustness and effectiveness.

Study registration

CRD42015023756 (PROSPERO)



5

Chapter 5

116

Abstract

Background

Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs,including the different components of artemisinin-based combination therapy (ACT).However, small sample sizes make it difficult to draw strong conclusions based on individualpharmacokinetic studies. The aim of this review is to summarize the evidence of theinfluence of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations.

MethodsA PROSPERO-registered systematic review to identify clinical trials that investigated theinfluence of pregnancy on the pharmacokinetic properties of different forms of ACT wasconducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed,Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, BiosisPreviews and the African Index Medicus were searched for studies published up toNovember 2015. The following components of ACT that are currently recommend by theWorld Health Organization as first-line treatment of malaria in pregnancy were reviewed:artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine,sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil.

ResultsThe literature search identified 121 reports, 27 original studies were included. 829 pregnantwomen were included in the analysis. Comparison of the available studies showed lowermaximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the activemetabolite of all artemisinin derivatives, after oral administration of artemether, artesunateand dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seenin lumefantrine studies, indicating a low exposure and possibly reduced efficacy. Theinfluence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant.Sulfadoxine plasma concentration was significantly reduced and clearance rates were higherin pregnancy, while pyrimethamine and mefloquine need more research as no generalconclusion can be drawn based on the available evidence. For atovaquone, the available datashowed a lower maximum concentration and exposure. Finally, the maximum concentrationof cycloguanil, the active metabolite of proguanil, was significantly lower, possiblycompromising the efficacy.


117

ConclusionThese findings suggest that reassessment of the dose of the artemisinin derivate and somecomponents of ACT are necessary to ensure the highest possible efficacy of malariatreatment in pregnant women. However, for most components of ACT, data were insufficientand extensive research with larger sample sizes will be necessary to identify the exactinfluences of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations. In addition, different clinical studies used diverse study designs with variousreported relevant outcomes. Future pharmacokinetic studies could benefit from moreuniform designs, in order to increase quality, robustness and effectiveness.

Study registration

CRD42015023756 (PROSPERO)



Chapter 5

118

Background

Malaria infection during pregnancy remains an important public health problem withpotential life-threatening risks for the pregnant woman, the foetus and the newborn child.403,

404 According to a systematic review to assess the burden of malaria in pregnancy,approximately 25 million pregnant women are at risk of Plasmodium falciparum infectionevery year.405 One in four women have evidence of placental infection at the time of delivery;of which a small fraction is encountered as an imported condition in non-endemic countriesin migrants and travellers.406 Imported cases of malaria in pregnancy are mainly P.falciparum acquired in sub-Saharan Africa.406 Malaria in pregnancy is caused by all fivespecies of Plasmodium infecting humans: P. falciparum, P. vivax, P. ovale, P.malariae and P. knowlesi. Most morbidity and mortality is caused by falciparum and vivaxmalaria. Plasmodium knowlesi malaria is endemic in parts of South East Asia and isrelatively rare in pregnancy.

Pregnancy increases the risk of both falciparum and vivax malaria.405, 407 The increasedsusceptibility has been attributed to broad hormonal and immunological changes that occurduring pregnancy.407 For P. falciparum, there is evidence that the increased susceptibility isdue to the lack of immunity to antigens expressed only by parasites infecting pregnantwomen.407, 408 It is unclear what causes the increased susceptibility for P. vivax malaria inpregnancy.407 The prevalence of both falciparum and vivax malaria is higher inprimigravidae than in non-pregnant women or multigravidae. As well, younger age isassociated with higher risk for malaria in pregnancy.405, 407 Plasmodium falciparum and P.vivax malaria are associated with maternal anaemia, lower birth weight and, in low-transmission areas, increased risks of spontaneous abortion, severe malaria and stillbirth.405,

409-412 The increased burden of malaria in pregnancy has been attributed to higher parasitedensities and the sequestration of P. falciparum infected erythrocytes (Pf-IEs) in theplacenta,405, 407, 408, 413-415 resulting in placental changes including inflammation anddisposition of pigment in fibrin or inflammatory cells, syncytial knotting and thickening ofthe trophoblastic basement membrane.407 Plasmodium vivax however, does not cytoadherein the placenta, but is associated with maternal anaemia and low birth weight.405

In order to reduce the burden of malaria in pregnancy, the WHO recommends a three-pronged approach. Women are recommended to sleep under long-lasting insecticide-impregnated nets (LLINs) and to use intermittent preventive treatment (IPTp) withsulfadoxine-pyrimethamine (SP) when living in areas with a high to moderate stabletransmission. The WHO emphasizes the importance of prompt diagnosis and effective casemanagement of malaria infections.416 Furthermore, all pregnant women should receive ironand folic acid supplementation as a part of routine antenatal care.


119

In the “Guidelines for the treatment of malaria” (3rd edition, 2015), the WHO recommends38

the use of an artemisinin-based combination therapy (ACT) for the treatment ofuncomplicated falciparum malaria in the 2nd and 3rd trimester of pregnancy.417 Over thepast two decades multiple studies have been conducted to assess the efficacy and safety ofACT in the 2nd and 3rd trimester of pregnancy compared to other treatments.247-249, 252, 253,

262, 265, 418 However, pregnancy is known to cause physiologic and pharmacokinetic changesthat might influence the efficacy of drugs. Different organ systems undergo changes whichresult in pharmacokinetic changes.419 Pregnancy is associated with significantcardiovascular changes, especially in the first trimester of pregnancy. Cardiac output, strokevolume and heart rate increase, systemic and pulmonary vascular resistance decrease, as wellas colloid osmotic pressure and haemoglobin concentration. This can increase the volume ofdistribution of hydrophilic substrates. Clinically, pregnant women sometimes need higherinitial and subsequent dosage regimens, especially for hydrophilic drugs. In contrast, drugsthat are bound to proteins or albumin can double the fraction of active pharmaceuticalfraction. Respiratory changes in pregnancy include increased pulmonary vascularity, tidalvolumes, minute volumes. In later stages of pregnancy, lung capacity may decrease becauseof the pressure from a big uterus on the diaphragm, causing alveolar collapse and atelectasis.In addition, pH of maternal blood may be increased, resulting in lower serum bicarbonateconcentration and a lower buffering capacity. Furthermore, a rightward shift of the oxy-haemoglobin dissociation curve may affect protein binding of some drugs. Also the renalsystem is altered by pregnancy. In the first halve of pregnancy, the renal blood flow andGFR (glomerular filtration rate) is increased. Elimination rates can be higher for renalcleared drugs resulting in shorter half-lives. The bioavailability (e.g. Cmax, T1/2, Tmax) of oralanti-malarial drugs can also be changed by gastro-intestinal changes during pregnancy.There is delayed gastric emptying, and a longer small-bowel transit duration. These factorsmainly influence single dose malaria treatments. Nausea and vomiting, common in earlypregnancy, can also change the bioavailability of the anti-malarial drug caused by lowerplasma concentrations. Also (sex) hormones during pregnancy increase or decrease theplasma concentrations of anti-malarial drugs. In the liver for example, CYP3A4 andcytochrome P450 are upregulated, resulting in a changed metabolism of CYP3A4metabolized drugs (e.g. lumefantrine). Many other mechanisms have been described,however, the most important changes include increased maternal fat and total body water,decreased plasma protein concentrations, increased maternal blood volume and cardiacoutput and altered activity of hepatic drug-metabolizing enzymes.419

Multiple studies have been conducted to study the influence of pregnancy onpharmacokinetic properties of ACT. However, due to small sample sizes it is often hard todraw strong conclusions based on these individual studies.10, 420



5

Chapter 5

118

Background

Malaria infection during pregnancy remains an important public health problem withpotential life-threatening risks for the pregnant woman, the foetus and the newborn child.403,

404 According to a systematic review to assess the burden of malaria in pregnancy,approximately 25 million pregnant women are at risk of Plasmodium falciparum infectionevery year.405 One in four women have evidence of placental infection at the time of delivery;of which a small fraction is encountered as an imported condition in non-endemic countriesin migrants and travellers.406 Imported cases of malaria in pregnancy are mainly P.falciparum acquired in sub-Saharan Africa.406 Malaria in pregnancy is caused by all fivespecies of Plasmodium infecting humans: P. falciparum, P. vivax, P. ovale, P.malariae and P. knowlesi. Most morbidity and mortality is caused by falciparum and vivaxmalaria. Plasmodium knowlesi malaria is endemic in parts of South East Asia and isrelatively rare in pregnancy.

Pregnancy increases the risk of both falciparum and vivax malaria.405, 407 The increasedsusceptibility has been attributed to broad hormonal and immunological changes that occurduring pregnancy.407 For P. falciparum, there is evidence that the increased susceptibility isdue to the lack of immunity to antigens expressed only by parasites infecting pregnantwomen.407, 408 It is unclear what causes the increased susceptibility for P. vivax malaria inpregnancy.407 The prevalence of both falciparum and vivax malaria is higher inprimigravidae than in non-pregnant women or multigravidae. As well, younger age isassociated with higher risk for malaria in pregnancy.405, 407 Plasmodium falciparum and P.vivax malaria are associated with maternal anaemia, lower birth weight and, in low-transmission areas, increased risks of spontaneous abortion, severe malaria and stillbirth.405,

409-412 The increased burden of malaria in pregnancy has been attributed to higher parasitedensities and the sequestration of P. falciparum infected erythrocytes (Pf-IEs) in theplacenta,405, 407, 408, 413-415 resulting in placental changes including inflammation anddisposition of pigment in fibrin or inflammatory cells, syncytial knotting and thickening ofthe trophoblastic basement membrane.407 Plasmodium vivax however, does not cytoadherein the placenta, but is associated with maternal anaemia and low birth weight.405

In order to reduce the burden of malaria in pregnancy, the WHO recommends a three-pronged approach. Women are recommended to sleep under long-lasting insecticide-impregnated nets (LLINs) and to use intermittent preventive treatment (IPTp) withsulfadoxine-pyrimethamine (SP) when living in areas with a high to moderate stabletransmission. The WHO emphasizes the importance of prompt diagnosis and effective casemanagement of malaria infections.416 Furthermore, all pregnant women should receive ironand folic acid supplementation as a part of routine antenatal care.


119

In the “Guidelines for the treatment of malaria” (3rd edition, 2015), the WHO recommends38

the use of an artemisinin-based combination therapy (ACT) for the treatment ofuncomplicated falciparum malaria in the 2nd and 3rd trimester of pregnancy.417 Over thepast two decades multiple studies have been conducted to assess the efficacy and safety ofACT in the 2nd and 3rd trimester of pregnancy compared to other treatments.247-249, 252, 253,

262, 265, 418 However, pregnancy is known to cause physiologic and pharmacokinetic changesthat might influence the efficacy of drugs. Different organ systems undergo changes whichresult in pharmacokinetic changes.419 Pregnancy is associated with significantcardiovascular changes, especially in the first trimester of pregnancy. Cardiac output, strokevolume and heart rate increase, systemic and pulmonary vascular resistance decrease, as wellas colloid osmotic pressure and haemoglobin concentration. This can increase the volume ofdistribution of hydrophilic substrates. Clinically, pregnant women sometimes need higherinitial and subsequent dosage regimens, especially for hydrophilic drugs. In contrast, drugsthat are bound to proteins or albumin can double the fraction of active pharmaceuticalfraction. Respiratory changes in pregnancy include increased pulmonary vascularity, tidalvolumes, minute volumes. In later stages of pregnancy, lung capacity may decrease becauseof the pressure from a big uterus on the diaphragm, causing alveolar collapse and atelectasis.In addition, pH of maternal blood may be increased, resulting in lower serum bicarbonateconcentration and a lower buffering capacity. Furthermore, a rightward shift of the oxy-haemoglobin dissociation curve may affect protein binding of some drugs. Also the renalsystem is altered by pregnancy. In the first halve of pregnancy, the renal blood flow andGFR (glomerular filtration rate) is increased. Elimination rates can be higher for renalcleared drugs resulting in shorter half-lives. The bioavailability (e.g. Cmax, T1/2, Tmax) of oralanti-malarial drugs can also be changed by gastro-intestinal changes during pregnancy.There is delayed gastric emptying, and a longer small-bowel transit duration. These factorsmainly influence single dose malaria treatments. Nausea and vomiting, common in earlypregnancy, can also change the bioavailability of the anti-malarial drug caused by lowerplasma concentrations. Also (sex) hormones during pregnancy increase or decrease theplasma concentrations of anti-malarial drugs. In the liver for example, CYP3A4 andcytochrome P450 are upregulated, resulting in a changed metabolism of CYP3A4metabolized drugs (e.g. lumefantrine). Many other mechanisms have been described,however, the most important changes include increased maternal fat and total body water,decreased plasma protein concentrations, increased maternal blood volume and cardiacoutput and altered activity of hepatic drug-metabolizing enzymes.419

Multiple studies have been conducted to study the influence of pregnancy onpharmacokinetic properties of ACT. However, due to small sample sizes it is often hard todraw strong conclusions based on these individual studies.10, 420



Chapter 5

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Objectives

The overall objective of this review was to summarize available evidence of the influence ofpregnancy on the pharmacokinetic properties of different artemisinin-based combinationsand the consequences these influences have on treatment dose and regime. The last reviewon this subject was published in 2009.421 The primary outcomes of interest for the analysisof the pharmacokinetics of the drugs in pregnancy were Cmax, Tmax, CL/F, V/F, T1/2 and totalexposure (Area Under the Curve: AUC).

MethodsThis review was conducted in June 2015. The last search was conducted on 10 November2015. Objectives and inclusion criteria were specified in advance and documented in aprotocol. Recommendations made by the Preferred Reporting Items for Systematic Reviewsand Meta-Analyses (PRISMA) group were followed.111 This review was registered inadvance in PROSPERO (International prospective register of systematic reviews).Registration number: CRD42015023756. An overview of ongoing or future trials is providedin Additional file 2 (additional file 1 is integrated in the methods section of this chapter).The costs of this literature study are not reported.402 The first and second author searched theelectronic databases Ovid Medline (1946 to November 2015), Ovid Embase (1947 toNovember 2015), Cochrane Central Register of Controlled Trials (November 2015), Web ofScience (1975 to November 2015), CINAHL Plus with Full Text (1937 to November 2015),African Index Medicus (1933 to November 2015), African Journals Online (AJOL) (frominception to November 2015), Google Scholar (without patents and citations), BiosisPreviews (1993 to November 2015) and PubMed (non-MEDLINE citations) (1947 toNovember 2015) to identify studies investigating the pharmacokinetics of ACTs in pregnantwomen. Also, major trial registries were searched to identify ongoing or future trials(Additional File 2). The search strategy consisted of free-text words and subject headingsrelated to pregnancy, malaria and seven different components of ACTs. The search strategyfor PubMed is depicted below. The search strategy was not limited by study design orlanguage. Only human studies were included. Unpublished data (e.g. conference or meetingabstracts) were excluded. The bibliographies of all identified articles were examined toidentify additional studies that were not identified during the computerized search. EndnoteX7.1 (Thomson Reuters) was used to manage, de-duplicate and screen the references foreligibility. Studies retrieved were eligible for inclusion if they satisfied all selection criteria.The study population consisted of pregnant females with malaria (P. falciparum, P. ovale,P. vivax, P. malariae & P. knowlesi) of all age groups. Treatment consisted of an artemisininderivate or artemisinin combination treatment. Furthermore, data was available to assess thepharmacokinetics of either artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) oratovaquone-proguanil (AP). Both studies performing a compartmental and a non-


121

compartmental analysis were included in the review. Eligibility assessment of studies foundwas performed independently in an unblinded standardized manner by the first two authors.The first author extracted the following study characteristics: first author, year ofpublication, geographic location, time of the study, type of study, administered drug anddosing regimen, the pharmacokinetic sampling regimen, drug quantification method,pharmacokinetic analytic methodology, number of pregnant and non-pregnant womentreated with the drug, population characteristics including age, weight and estimatedgestational age (EGA), pharmacokinetic outcome measurements including total dose, Cmax,Cmax/dose, Tmax, oral plasma clearance rate (CL/F), apparent volume of distribution (V/F),t1/2, day 7, 14 and 28 concentrations and exposure (Area Under the Curve; AUC) overmultiple time spans for both pregnant and non-pregnant women and conclusion of thearticles. Data was double checked for all articles included in the qualitative synthesis by thesecond author. A validity assessment was performed by the first author using the Downs andBlack checklist for measuring study quality.422 Details are included in Additional file 3:Quality of included studies. In short, articles were scored for quality of reporting, externalvalidity, internal validity (bias and confounding) and statistical power. Quality was classifiedwith 0 (poor) to 31 points (excellent).

The included studies were separated in nine groups based on the type of drug administered.These nine groups were: artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) andatovaquone-proguanil (AP). Some studies were used in multiple groups. Within each group,results were compared, and a general conclusion was drawn. These groups represent thecomponents of first line drug therapies recommended by the WHO for pregnant women inthe second and third trimester for the treatment of uncomplicated P. falciparum treatment(artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-SPand DHA-PPQ), of drugs recommended for intermittent preventive treatment in pregnancy(IPTp) (SP) and as prophylaxis for travellers (AP).38, 423 In the first trimester of pregnancy,the WHO recommends the use of 7 days with quinine plus clindamycin (10mg/kg bw twicea day) for the treatment of uncomplicated P. falciparum malaria (“strong recommendation”).An ACT or oral artesunate + clindamycin is an acceptable alternative if quinine +clindamycin is not available or is ineffective. These drugs are not included in this systematicreview. The full PubMed search strategy was as follows: 1. "Malaria"[MeSH] OR"Plasmodium"[MeSH] OR "malaria"[tiab] OR "plasmodium"[tiab] AND2."Pregnancy"[MeSH] OR "Pregnan*"[tiab] AND 3."pharmacokinetics"[sh] OR"pharmacokinetics"[MeSH] OR "pharmacokinetic*"[tiab] OR “pharmacokinetics*”[tiab]AND 4. ("artemisinin*"[tiab] OR "artesunate*"[tiab] OR "artemether*"[tiab] OR"dihydroartemisinin*"[tiab]) OR 5. ("lumefantrine"[Supplementary Concept] OR"artemether-lumefantrine combination"[Supplementary Concept] OR"lumefantrine*"[tiab]) OR 6. ("Mefloquine"[Mesh] OR "Ro 21-5104"[SupplementaryConcept] OR "mefloquine-sulfadoxine-pyrimethamine"[Supplementary Concept] OR



5

Chapter 5

120

Objectives

The overall objective of this review was to summarize available evidence of the influence ofpregnancy on the pharmacokinetic properties of different artemisinin-based combinationsand the consequences these influences have on treatment dose and regime. The last reviewon this subject was published in 2009.421 The primary outcomes of interest for the analysisof the pharmacokinetics of the drugs in pregnancy were Cmax, Tmax, CL/F, V/F, T1/2 and totalexposure (Area Under the Curve: AUC).

MethodsThis review was conducted in June 2015. The last search was conducted on 10 November2015. Objectives and inclusion criteria were specified in advance and documented in aprotocol. Recommendations made by the Preferred Reporting Items for Systematic Reviewsand Meta-Analyses (PRISMA) group were followed.111 This review was registered inadvance in PROSPERO (International prospective register of systematic reviews).Registration number: CRD42015023756. An overview of ongoing or future trials is providedin Additional file 2 (additional file 1 is integrated in the methods section of this chapter).The costs of this literature study are not reported.402 The first and second author searched theelectronic databases Ovid Medline (1946 to November 2015), Ovid Embase (1947 toNovember 2015), Cochrane Central Register of Controlled Trials (November 2015), Web ofScience (1975 to November 2015), CINAHL Plus with Full Text (1937 to November 2015),African Index Medicus (1933 to November 2015), African Journals Online (AJOL) (frominception to November 2015), Google Scholar (without patents and citations), BiosisPreviews (1993 to November 2015) and PubMed (non-MEDLINE citations) (1947 toNovember 2015) to identify studies investigating the pharmacokinetics of ACTs in pregnantwomen. Also, major trial registries were searched to identify ongoing or future trials(Additional File 2). The search strategy consisted of free-text words and subject headingsrelated to pregnancy, malaria and seven different components of ACTs. The search strategyfor PubMed is depicted below. The search strategy was not limited by study design orlanguage. Only human studies were included. Unpublished data (e.g. conference or meetingabstracts) were excluded. The bibliographies of all identified articles were examined toidentify additional studies that were not identified during the computerized search. EndnoteX7.1 (Thomson Reuters) was used to manage, de-duplicate and screen the references foreligibility. Studies retrieved were eligible for inclusion if they satisfied all selection criteria.The study population consisted of pregnant females with malaria (P. falciparum, P. ovale,P. vivax, P. malariae & P. knowlesi) of all age groups. Treatment consisted of an artemisininderivate or artemisinin combination treatment. Furthermore, data was available to assess thepharmacokinetics of either artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) oratovaquone-proguanil (AP). Both studies performing a compartmental and a non-


121

compartmental analysis were included in the review. Eligibility assessment of studies foundwas performed independently in an unblinded standardized manner by the first two authors.The first author extracted the following study characteristics: first author, year ofpublication, geographic location, time of the study, type of study, administered drug anddosing regimen, the pharmacokinetic sampling regimen, drug quantification method,pharmacokinetic analytic methodology, number of pregnant and non-pregnant womentreated with the drug, population characteristics including age, weight and estimatedgestational age (EGA), pharmacokinetic outcome measurements including total dose, Cmax,Cmax/dose, Tmax, oral plasma clearance rate (CL/F), apparent volume of distribution (V/F),t1/2, day 7, 14 and 28 concentrations and exposure (Area Under the Curve; AUC) overmultiple time spans for both pregnant and non-pregnant women and conclusion of thearticles. Data was double checked for all articles included in the qualitative synthesis by thesecond author. A validity assessment was performed by the first author using the Downs andBlack checklist for measuring study quality.422 Details are included in Additional file 3:Quality of included studies. In short, articles were scored for quality of reporting, externalvalidity, internal validity (bias and confounding) and statistical power. Quality was classifiedwith 0 (poor) to 31 points (excellent).

The included studies were separated in nine groups based on the type of drug administered.These nine groups were: artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) andatovaquone-proguanil (AP). Some studies were used in multiple groups. Within each group,results were compared, and a general conclusion was drawn. These groups represent thecomponents of first line drug therapies recommended by the WHO for pregnant women inthe second and third trimester for the treatment of uncomplicated P. falciparum treatment(artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-SPand DHA-PPQ), of drugs recommended for intermittent preventive treatment in pregnancy(IPTp) (SP) and as prophylaxis for travellers (AP).38, 423 In the first trimester of pregnancy,the WHO recommends the use of 7 days with quinine plus clindamycin (10mg/kg bw twicea day) for the treatment of uncomplicated P. falciparum malaria (“strong recommendation”).An ACT or oral artesunate + clindamycin is an acceptable alternative if quinine +clindamycin is not available or is ineffective. These drugs are not included in this systematicreview. The full PubMed search strategy was as follows: 1. "Malaria"[MeSH] OR"Plasmodium"[MeSH] OR "malaria"[tiab] OR "plasmodium"[tiab] AND2."Pregnancy"[MeSH] OR "Pregnan*"[tiab] AND 3."pharmacokinetics"[sh] OR"pharmacokinetics"[MeSH] OR "pharmacokinetic*"[tiab] OR “pharmacokinetics*”[tiab]AND 4. ("artemisinin*"[tiab] OR "artesunate*"[tiab] OR "artemether*"[tiab] OR"dihydroartemisinin*"[tiab]) OR 5. ("lumefantrine"[Supplementary Concept] OR"artemether-lumefantrine combination"[Supplementary Concept] OR"lumefantrine*"[tiab]) OR 6. ("Mefloquine"[Mesh] OR "Ro 21-5104"[SupplementaryConcept] OR "mefloquine-sulfadoxine-pyrimethamine"[Supplementary Concept] OR



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"mefloquine*"[tiab] OR "Lariam"[tiab] OR "ASMQ"[tiab] OR "artesunate-mefloquine"[tiab]) OR 7. ("Amodiaquine"[Mesh] OR "amodiaquine, artesunate drugcombination"[Supplementary Concept] OR "amodiaquine*"[tiab] OR "AQ*"[tiab]) OR 8.(("sulfadoxine-pyrimethamine-artesunate"[Supplementary Concept] OR "fanasil,pyrimethamine drug combination"[Supplementary Concept]) OR "SP"[tiab] OR(("sulfadoxine*"[tiab] OR "sulphadoxine*"[tiab]) AND "pyrimethamine*"[tiab])) OR 9.("piperaquine"[Supplementary Concept] OR "piperaquine*"[tiab]) OR 10. ("atovaquone,proguanil drug combination"[Supplementary Concept] OR "Atovaquone"[Mesh] OR"atovaquone*"[tiab] OR "Proguanil"[Mesh] OR "proguanil*"[tiab] OR "malarone*"[tiab])

ResultsThe initial search yielded 121 records (Fig. 1: PRISMA flow diagram of study selection). 27articles met the inclusion criteria and were included in the analysis (Table 1).241, 248, 251, 253,

256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-434 The main study findings of the included trials can befound in Table 2.

The studies included were published between 1990 and 2015 and included a total of 829pregnant and 377 non-pregnant patients. Articles were categorized by the drug that wasevaluated. If more than one anti-malarial was administered, the study was included in bothcategories. In total, 34 patients received artemether (34 pregnant; 0 non-pregnant), 182artesunate (AS) (94 pregnant; 88 non-pregnant), 48 DHA (56 pregnant, 57 non-pregnant),341 lumefantrine (324 pregnant; 17 non-pregnant), 46 amodiaquine (27 pregnant, 19 non-pregnant), 85 mefloquine (53 pregnant; 32 non-pregnant), 279 SP (161 pregnant; 118 non-pregnant), 72 PPQ (68 pregnant; 69 non-pregnant) and 163 AP (105 pregnant, 58 non-pregnant).

Quality assessment of the included studiesDetails of the quality assessment are depicted in the table in Additional file 3. In summary,studies were given a median 23 points (range 16–29) out of 31. Most of the studies did notreport how patients were selected and did not report the percentage of patients who agreedto participate. This could compromise the representativeness of the study population. Therewas no blinding of patients, researchers or statistical analysis. Overall, the quality of theincluded studies could be evaluated as moderate to good.

Studies assessing the pharmacokinetics of ACTThe data sheet (excel file) of the included studies is provided as Additional file 4.


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Artemether and dihydroartemisininTwo studies investigated the pharmacokinetic properties of artemether in pregnant women,following oral administration of artemether-lumefantrine (AL) (80/480 mg b.i.d. for3 days).251, 258 Tarning et al.258 studied 21 pregnant women in the second or third trimesterof pregnancy with uncomplicated falciparum malaria. Both a compartmental (zero-orderabsorption followed by transit compartment absorption and a simultaneous one-compartment drug-metabolite model) and a noncompartmental analysis were performed.The first revealed no statistically significant covariates, indicating among others nodifference between second and third trimester. Results obtained by noncompartmentalanalysis were used to compare the pharmacokinetic properties of pregnant women with theliterature. Estimated exposure to artemether and its active metabolite DHA was similar tothat reported in pregnant Thai patients251 but lower than that reported in two studies in adultnon-pregnant patients from Thailand.127, 435 However, these results should be interpretedwith caution since ethnicity might have an impact on the pharmacokinetic properties of thesedrugs.

McGready et al.251 studied 13 women in the second and third trimester of pregnancy withrecrudescent uncomplicated multi-drug resistant falciparum malaria after 7-day quininetreatment. A noncompartmental analysis revealed no significant differences in thepharmacokinetic parameters of artemether and DHA between the second and third trimester.Comparison with data from the literature showed a lower exposure (AUC) and maximumconcentration (Cmax) of artemether compared to male Thai patients and of DHA comparedto non-pregnant patients.127

Artesunate and dihydroartemisininSix studies investigated the pharmacokinetics after administration of AS.241, 312, 316, 425, 427, 436

Three studies described the pharmacokinetic properties of AS as well as the pharmacokineticproperties of DHA, the active metabolite of AS, that is the principle source of anti-malarialactivity after AS administration.241, 425 McGready et al.241 compared the pharmacokinetics ofintravenous and oral AS in 20 women with malaria during pregnancy and 3 months post-partum without malaria. They found no significant differences in AS or DHApharmacokinetics after intravenous administration. After oral administration, the exposureof AS and DHA (AUC) was significantly higher in pregnant women with malaria than inpost-partum women without malaria. This can be explained by a higher bioavailability andlower oral clearance. The authors ascribed the differences to a disease related reduction inpre-systemic metabolism, as an active malaria infection tends to increase oral bioavailability,and not to the pregnancy. This assumption was supported by a decrease in DHA exposure atday 6 compared with day 0 and 1 in women with malaria but not in healthy women.



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"mefloquine*"[tiab] OR "Lariam"[tiab] OR "ASMQ"[tiab] OR "artesunate-mefloquine"[tiab]) OR 7. ("Amodiaquine"[Mesh] OR "amodiaquine, artesunate drugcombination"[Supplementary Concept] OR "amodiaquine*"[tiab] OR "AQ*"[tiab]) OR 8.(("sulfadoxine-pyrimethamine-artesunate"[Supplementary Concept] OR "fanasil,pyrimethamine drug combination"[Supplementary Concept]) OR "SP"[tiab] OR(("sulfadoxine*"[tiab] OR "sulphadoxine*"[tiab]) AND "pyrimethamine*"[tiab])) OR 9.("piperaquine"[Supplementary Concept] OR "piperaquine*"[tiab]) OR 10. ("atovaquone,proguanil drug combination"[Supplementary Concept] OR "Atovaquone"[Mesh] OR"atovaquone*"[tiab] OR "Proguanil"[Mesh] OR "proguanil*"[tiab] OR "malarone*"[tiab])

ResultsThe initial search yielded 121 records (Fig. 1: PRISMA flow diagram of study selection). 27articles met the inclusion criteria and were included in the analysis (Table 1).241, 248, 251, 253,

256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-434 The main study findings of the included trials can befound in Table 2.

The studies included were published between 1990 and 2015 and included a total of 829pregnant and 377 non-pregnant patients. Articles were categorized by the drug that wasevaluated. If more than one anti-malarial was administered, the study was included in bothcategories. In total, 34 patients received artemether (34 pregnant; 0 non-pregnant), 182artesunate (AS) (94 pregnant; 88 non-pregnant), 48 DHA (56 pregnant, 57 non-pregnant),341 lumefantrine (324 pregnant; 17 non-pregnant), 46 amodiaquine (27 pregnant, 19 non-pregnant), 85 mefloquine (53 pregnant; 32 non-pregnant), 279 SP (161 pregnant; 118 non-pregnant), 72 PPQ (68 pregnant; 69 non-pregnant) and 163 AP (105 pregnant, 58 non-pregnant).

Quality assessment of the included studiesDetails of the quality assessment are depicted in the table in Additional file 3. In summary,studies were given a median 23 points (range 16–29) out of 31. Most of the studies did notreport how patients were selected and did not report the percentage of patients who agreedto participate. This could compromise the representativeness of the study population. Therewas no blinding of patients, researchers or statistical analysis. Overall, the quality of theincluded studies could be evaluated as moderate to good.

Studies assessing the pharmacokinetics of ACTThe data sheet (excel file) of the included studies is provided as Additional file 4.


123

Artemether and dihydroartemisininTwo studies investigated the pharmacokinetic properties of artemether in pregnant women,following oral administration of artemether-lumefantrine (AL) (80/480 mg b.i.d. for3 days).251, 258 Tarning et al.258 studied 21 pregnant women in the second or third trimesterof pregnancy with uncomplicated falciparum malaria. Both a compartmental (zero-orderabsorption followed by transit compartment absorption and a simultaneous one-compartment drug-metabolite model) and a noncompartmental analysis were performed.The first revealed no statistically significant covariates, indicating among others nodifference between second and third trimester. Results obtained by noncompartmentalanalysis were used to compare the pharmacokinetic properties of pregnant women with theliterature. Estimated exposure to artemether and its active metabolite DHA was similar tothat reported in pregnant Thai patients251 but lower than that reported in two studies in adultnon-pregnant patients from Thailand.127, 435 However, these results should be interpretedwith caution since ethnicity might have an impact on the pharmacokinetic properties of thesedrugs.

McGready et al.251 studied 13 women in the second and third trimester of pregnancy withrecrudescent uncomplicated multi-drug resistant falciparum malaria after 7-day quininetreatment. A noncompartmental analysis revealed no significant differences in thepharmacokinetic parameters of artemether and DHA between the second and third trimester.Comparison with data from the literature showed a lower exposure (AUC) and maximumconcentration (Cmax) of artemether compared to male Thai patients and of DHA comparedto non-pregnant patients.127

Artesunate and dihydroartemisininSix studies investigated the pharmacokinetics after administration of AS.241, 312, 316, 425, 427, 436

Three studies described the pharmacokinetic properties of AS as well as the pharmacokineticproperties of DHA, the active metabolite of AS, that is the principle source of anti-malarialactivity after AS administration.241, 425 McGready et al.241 compared the pharmacokinetics ofintravenous and oral AS in 20 women with malaria during pregnancy and 3 months post-partum without malaria. They found no significant differences in AS or DHApharmacokinetics after intravenous administration. After oral administration, the exposureof AS and DHA (AUC) was significantly higher in pregnant women with malaria than inpost-partum women without malaria. This can be explained by a higher bioavailability andlower oral clearance. The authors ascribed the differences to a disease related reduction inpre-systemic metabolism, as an active malaria infection tends to increase oral bioavailability,and not to the pregnancy. This assumption was supported by a decrease in DHA exposure atday 6 compared with day 0 and 1 in women with malaria but not in healthy women.



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Kloprogge et al.436 used the same data as McGready et al. but used a noncompartmentalanalysis to dissect and quantify the individual contributions of malaria and pregnancy to thealtered pharmacokinetics. They found no effect of both malaria and pregnancy onpharmacokinetic properties of intravenous AS and DHA. However, their research showedopposite and independent effects for malaria (87 % increase) and pregnancy (23 % decrease)on the absolute oral bioavailability of artesunate. Both findings are in line with conclusionsdrawn by McGready et al. and ask for further dose optimization studies.

Valea et al.425 studied the pharmacokinetics of AS and DHA in 24 pregnant women and 24controls. They found a significantly lower oral clearance (CL/F) and higher exposure (AUC)of AS in pregnant women compared to the non-pregnant women. However, they did not findsignificant differences for DHA. It is important to notice that there was a significantly higherparasite density in the pregnant women’ group, possibly resulting in higher exposure, whichmight have masked the pregnancy-related effects.

Three other studies reported only the pharmacokinetic properties of DHA.312, 316, 427

Onyamboko et al.427 compared 26 pregnant women with malaria with the same women threemonths post-partum and with 25 non-pregnant parasitaemic controls. After a single dose oforally administred AS, there appeared to be no significant and clinically relevant differencesin DHA pharmacokinetics between the women in pregnant and post-partum state. However,the exposure of DHA (AUCfree) was significantly lower in pregnant women compared tonon-pregnant controls (the authors used a 90 % confidence interval), which is consistent witha significantly increased clearance (CL/F) in the pregnant group. The authors described acouple of reasons for this apparent difference between pregnant women and non-pregnantcontrols and the absence of this difference between pregnant and post-partum women,namely that the physiological changes that occur during pregnancy might remain 3 monthspost-partum, that lactation influences pharmacokinetics, that most post-partum women werenot parasitaemic and that a comparison in the same women mitigates the effects of potentialother confounders.

The investigation by Morris et al.312 is based on the same clinical study, but used acompartmental analysis (one compartmental analysis with mixed zero order, lagged first-order absorption for AS) instead of a non-compartmental analysis to describe the data. In thefinal model, pregnancy status was the only covariate that had a significant influence on DHAclearance, suggesting a faster clearance of DHA in pregnant women. Together with the datafrom Onyamboko et al., the authors conclude that this provides further evidence that higherdoses of AS would be required in pregnant women. Another study by McGready et al.316

from 2006 (n = 24) showed lower exposure (AUC) to DHA and higher rates of clearanceand apparent volume of distribution in pregnant women compared to literature on non-


125

pregnant women, although this should be interpreted with caution as differences inmethodology of the studies might explain (part of) the differences.437

DihydroartemisininThree articles report the pharmacokinetic properties of oral DHA.267, 268, 434 Rijken et al. andTarning et al. papers are based on one study into the pharmacokinetics of DHA after the oraladministration of DHA-PQ (6.4 and 51.2 mg/kg p.o. q.d. for 3 days).267, 268 Rijken et al.267

used a noncompartmental analysis to describe the pharmacokinetic properties in 24 pregnantwomen and 24 controls with acute falciparum malaria. They report no significant differencesin total DHA exposure or maximum concentration between the two groups, although theDHA exposure after the first dose was significantly lower among the pregnant women, andthere was seemingly a trend of lower exposure after the other doses. As well, there was atrend towards higher clearance in pregnant women, but this did not reach statisticalsignificance. However, the authors warn for the potentially masking effect of the high inter-individual variability.

Using a mono-compartmental disposition model, Tarning et al.268 report a 38% lower totalexposure to DHA in pregnant women compared to the controls (p = 0.001), consistent witha significantly higher apparent volume of distribution (p = 0.008) and clearance rate(p = 0.001). This could be explained by pregnancy related induction of hepaticglucuronidation enzymes resulting in an increased first-pass metabolism and acceleratedclearance.

Benjamin et al.434 report no differences in pharmacokinetic properties of DHA betweenpregnant and non-pregnant women without malaria after oral DHA-PQ (7 and 58 mg/kg q.d.for 3 days).

LumefantrineThe pharmacokinetic properties of lumefantrine were investigated in six studies.248, 251, 253,

315, 426, 438 A study by McGready et al.251 in 13 pregnant women with recrudescent falciparummalaria showed significantly lower lumefantrine AUC values in pregnant women than innon-pregnant patients from studies with uncomplicated malaria, caused by more rapidlumefantrine elimination in pregnant women. The large proportion of smokers among thenon-pregnant patients made it difficult to draw strong conclusions on the cause of thisdifference. Also, they reported a proportion of 38 % of pregnant women with a day 7lumefantrine concentration below 280 ng/ml, which is associated with high failure rates(49%).439



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Kloprogge et al.436 used the same data as McGready et al. but used a noncompartmentalanalysis to dissect and quantify the individual contributions of malaria and pregnancy to thealtered pharmacokinetics. They found no effect of both malaria and pregnancy onpharmacokinetic properties of intravenous AS and DHA. However, their research showedopposite and independent effects for malaria (87 % increase) and pregnancy (23 % decrease)on the absolute oral bioavailability of artesunate. Both findings are in line with conclusionsdrawn by McGready et al. and ask for further dose optimization studies.

Valea et al.425 studied the pharmacokinetics of AS and DHA in 24 pregnant women and 24controls. They found a significantly lower oral clearance (CL/F) and higher exposure (AUC)of AS in pregnant women compared to the non-pregnant women. However, they did not findsignificant differences for DHA. It is important to notice that there was a significantly higherparasite density in the pregnant women’ group, possibly resulting in higher exposure, whichmight have masked the pregnancy-related effects.

Three other studies reported only the pharmacokinetic properties of DHA.312, 316, 427

Onyamboko et al.427 compared 26 pregnant women with malaria with the same women threemonths post-partum and with 25 non-pregnant parasitaemic controls. After a single dose oforally administred AS, there appeared to be no significant and clinically relevant differencesin DHA pharmacokinetics between the women in pregnant and post-partum state. However,the exposure of DHA (AUCfree) was significantly lower in pregnant women compared tonon-pregnant controls (the authors used a 90 % confidence interval), which is consistent witha significantly increased clearance (CL/F) in the pregnant group. The authors described acouple of reasons for this apparent difference between pregnant women and non-pregnantcontrols and the absence of this difference between pregnant and post-partum women,namely that the physiological changes that occur during pregnancy might remain 3 monthspost-partum, that lactation influences pharmacokinetics, that most post-partum women werenot parasitaemic and that a comparison in the same women mitigates the effects of potentialother confounders.

The investigation by Morris et al.312 is based on the same clinical study, but used acompartmental analysis (one compartmental analysis with mixed zero order, lagged first-order absorption for AS) instead of a non-compartmental analysis to describe the data. In thefinal model, pregnancy status was the only covariate that had a significant influence on DHAclearance, suggesting a faster clearance of DHA in pregnant women. Together with the datafrom Onyamboko et al., the authors conclude that this provides further evidence that higherdoses of AS would be required in pregnant women. Another study by McGready et al.316

from 2006 (n = 24) showed lower exposure (AUC) to DHA and higher rates of clearanceand apparent volume of distribution in pregnant women compared to literature on non-


125

pregnant women, although this should be interpreted with caution as differences inmethodology of the studies might explain (part of) the differences.437

DihydroartemisininThree articles report the pharmacokinetic properties of oral DHA.267, 268, 434 Rijken et al. andTarning et al. papers are based on one study into the pharmacokinetics of DHA after the oraladministration of DHA-PQ (6.4 and 51.2 mg/kg p.o. q.d. for 3 days).267, 268 Rijken et al.267

used a noncompartmental analysis to describe the pharmacokinetic properties in 24 pregnantwomen and 24 controls with acute falciparum malaria. They report no significant differencesin total DHA exposure or maximum concentration between the two groups, although theDHA exposure after the first dose was significantly lower among the pregnant women, andthere was seemingly a trend of lower exposure after the other doses. As well, there was atrend towards higher clearance in pregnant women, but this did not reach statisticalsignificance. However, the authors warn for the potentially masking effect of the high inter-individual variability.

Using a mono-compartmental disposition model, Tarning et al.268 report a 38% lower totalexposure to DHA in pregnant women compared to the controls (p = 0.001), consistent witha significantly higher apparent volume of distribution (p = 0.008) and clearance rate(p = 0.001). This could be explained by pregnancy related induction of hepaticglucuronidation enzymes resulting in an increased first-pass metabolism and acceleratedclearance.

Benjamin et al.434 report no differences in pharmacokinetic properties of DHA betweenpregnant and non-pregnant women without malaria after oral DHA-PQ (7 and 58 mg/kg q.d.for 3 days).

LumefantrineThe pharmacokinetic properties of lumefantrine were investigated in six studies.248, 251, 253,

315, 426, 438 A study by McGready et al.251 in 13 pregnant women with recrudescent falciparummalaria showed significantly lower lumefantrine AUC values in pregnant women than innon-pregnant patients from studies with uncomplicated malaria, caused by more rapidlumefantrine elimination in pregnant women. The large proportion of smokers among thenon-pregnant patients made it difficult to draw strong conclusions on the cause of thisdifference. Also, they reported a proportion of 38 % of pregnant women with a day 7lumefantrine concentration below 280 ng/ml, which is associated with high failure rates(49%).439



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The study by McGready et al. from 2006 was nested in a larger trial to assess the efficacy,safety, tolerability and pregnancy outcomes of AL in pregnant women.248 Apart from theseoutcomes, the study by McGready et al.248 from 2008 describes day 7 capillary plasmalumefantrine concentrations in 85 patients. In total, 35 % of patients had a day 7 capillaryplasma concentration below 355 ng/ml (which corresponds with 280 ng/ml in venousplasma). All 21 (100 %) patients with levels over 600 ng/ml were cured, while patients withlower values had recrudescent infections (p < 0.001).

A third study nested in the trial mentioned above investigated the populationpharmacokinetics of lumefantrine in 103 pregnant women with uncomplicated multidrug-resistant falciparum malaria.315 Using a two-compartment model with first-order absorptionand elimination, they predicted a 12 % odds increase in recrudescence and 7.2 % increase inapparent volume of distribution for each successive week of EGA on admission for pregnantwomen. Also, they showed a non-significant trend (p = 0.26) for the predicted day 7 mediancapillary lumefantrine concentrations to be lower in women with a recrudescent [n = 17;median concentration: 388 ng/ml (range 126–536)] or new infection [n = 21; medianconcentration: 377 ng/ml (range 136–1210)] compared to women who had no recrudescence[n = 65, median concentration: 427 ng/ml (range 135–1600)]. Based on different doseregime simulations using their final model, they recommend a 5-day regime instead of a 3-day regime to increase exposure to artemether and DHA and increase day 7 plasmalumefantrine concentration.

The study by Piola et al.253 reports the data of a large efficacy study conducted in 304pregnant women with uncomplicated falciparum malaria, of whom 152 received quinine and152 received AL. For 97 of the women who received AL, the day 7 plasma lumefantrineconcentration was available. 32 % of women had a lumefantrine concentration below280 ng/ml (venous plasma). Also the reappearance of malaria was significantly associatedwith decreased plasma concentrations of lumefantrine [Reappearance: 422 ng/ml (range 15–3246) vs no reappearance: 240 ng/ml (range 123–454); p = 0.01].

Nested into this efficacy trial was a pharmacokinetic study, which comparedpharmacokinetics of lumefantrine in pregnant (n = 26) and non-pregnant (n = 17) women.426

This study by Tarning et al. showed no statistical difference in total lumefantrine exposure,apparent volume of distribution of elimination clearance between the two groups. Tmax andT1/2were significantly shorter in pregnant women. The day 7 concentration of lumefantrinewas lower among pregnant women (488 ng/ml [range 30.7–3550] in pregnant women vs 720[range 339–2150] in non-pregnant women), but this difference was not statisticallysignificant (p = 0.128). Fifteen percent of the pregnant women had a day 7 lumefantrinevenous plasma concentration below 280 ng/ml, while none of the women in the non-pregnant control group had day 7 lumefantrine venous plasma concentrations below


127

280 ng/ml. With this in view, the study suggested no significant correlation between weekof EGA and drug exposure.

A third study, nested in the efficacy trial, was performed by Kloprogge et al.438 The samedata as Tarning et al. was used, plus day 7 capillary lumefantrine concentrations of 89pregnant women with P. falciparum malaria. Based on a transit-compartment absorptionmodel followed by a two-compartment disposition mode, a 27 % lower day 7 lumefantrineconcentration in pregnant women was found compared to non-pregnant women., caused bya 36.5 % decrease in intercompartmental clearance during pregnancy. Although thiscorresponded with a previous study in Thailand,251 the cure rate was higher in this study,possibly resulting from higher background immunity or less lumefantrine resistance inUganda compared to Thailand.

AmodiaquineThe pharmacokinetics of amodiaquine were investigated in two studies.259, 309 Rijken et al.259

reported no difference in pharmacokinetic parameters between pregnant women with P.vivax malaria (n = 24) and post-partum women (n = 19), except for the maximumconcentration (Cmax) of desethylamodiaquine (DEAQ), the principle metabolite ofamodiaquine, that was significantly lower in pregnant women (p = 0.019). However,because the difference was below 10 % and the total exposure to (desethyl)amodiaquine didnot differ significantly, the clinical impact of this difference was considered limited. Therewas no significant difference in pharmacokinetic parameters between the 2nd and 3rdtrimester of pregnancy. Also, there was no significant pharmacokinetic difference betweenpost-partum women with P. vivax malaria and those without it, making it unlikely that adisease effect masked the differences between pregnant and post-partum women. Pregnantwomen with recurrent P. vivax malaria did have a significantly lower dose-normalizedamodiaquine exposure than post-partum women (p = 0.036), suggesting that high drugexposure suppresses recurrent malaria.

Tarning et al.259 did a compartmental analysis of the same data using a lagged first-orderabsorption with a two-compartment disposition model followed by a three-compartmentdisposition of desethylamodiaquine. They found a relatively small effect of age ofamodiaquine clearance (1.36 % reduction per year), which might be related to an increasedimmunity in older patients and reflect reduced severity of the disease. Also, pregnant patientshad a reduced absorption lag time (41.6 % decrease), possibly as a result of increased cardiacoutput resulting in an increased blood flow to the stomach and small intestine.440 Neitherpregnancy status nor estimated gestational age resulted in a clinically relevant impact onother pharmacokinetic parameters.



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The study by McGready et al. from 2006 was nested in a larger trial to assess the efficacy,safety, tolerability and pregnancy outcomes of AL in pregnant women.248 Apart from theseoutcomes, the study by McGready et al.248 from 2008 describes day 7 capillary plasmalumefantrine concentrations in 85 patients. In total, 35 % of patients had a day 7 capillaryplasma concentration below 355 ng/ml (which corresponds with 280 ng/ml in venousplasma). All 21 (100 %) patients with levels over 600 ng/ml were cured, while patients withlower values had recrudescent infections (p < 0.001).

A third study nested in the trial mentioned above investigated the populationpharmacokinetics of lumefantrine in 103 pregnant women with uncomplicated multidrug-resistant falciparum malaria.315 Using a two-compartment model with first-order absorptionand elimination, they predicted a 12 % odds increase in recrudescence and 7.2 % increase inapparent volume of distribution for each successive week of EGA on admission for pregnantwomen. Also, they showed a non-significant trend (p = 0.26) for the predicted day 7 mediancapillary lumefantrine concentrations to be lower in women with a recrudescent [n = 17;median concentration: 388 ng/ml (range 126–536)] or new infection [n = 21; medianconcentration: 377 ng/ml (range 136–1210)] compared to women who had no recrudescence[n = 65, median concentration: 427 ng/ml (range 135–1600)]. Based on different doseregime simulations using their final model, they recommend a 5-day regime instead of a 3-day regime to increase exposure to artemether and DHA and increase day 7 plasmalumefantrine concentration.

The study by Piola et al.253 reports the data of a large efficacy study conducted in 304pregnant women with uncomplicated falciparum malaria, of whom 152 received quinine and152 received AL. For 97 of the women who received AL, the day 7 plasma lumefantrineconcentration was available. 32 % of women had a lumefantrine concentration below280 ng/ml (venous plasma). Also the reappearance of malaria was significantly associatedwith decreased plasma concentrations of lumefantrine [Reappearance: 422 ng/ml (range 15–3246) vs no reappearance: 240 ng/ml (range 123–454); p = 0.01].

Nested into this efficacy trial was a pharmacokinetic study, which comparedpharmacokinetics of lumefantrine in pregnant (n = 26) and non-pregnant (n = 17) women.426

This study by Tarning et al. showed no statistical difference in total lumefantrine exposure,apparent volume of distribution of elimination clearance between the two groups. Tmax andT1/2were significantly shorter in pregnant women. The day 7 concentration of lumefantrinewas lower among pregnant women (488 ng/ml [range 30.7–3550] in pregnant women vs 720[range 339–2150] in non-pregnant women), but this difference was not statisticallysignificant (p = 0.128). Fifteen percent of the pregnant women had a day 7 lumefantrinevenous plasma concentration below 280 ng/ml, while none of the women in the non-pregnant control group had day 7 lumefantrine venous plasma concentrations below


127

280 ng/ml. With this in view, the study suggested no significant correlation between weekof EGA and drug exposure.

A third study, nested in the efficacy trial, was performed by Kloprogge et al.438 The samedata as Tarning et al. was used, plus day 7 capillary lumefantrine concentrations of 89pregnant women with P. falciparum malaria. Based on a transit-compartment absorptionmodel followed by a two-compartment disposition mode, a 27 % lower day 7 lumefantrineconcentration in pregnant women was found compared to non-pregnant women., caused bya 36.5 % decrease in intercompartmental clearance during pregnancy. Although thiscorresponded with a previous study in Thailand,251 the cure rate was higher in this study,possibly resulting from higher background immunity or less lumefantrine resistance inUganda compared to Thailand.

AmodiaquineThe pharmacokinetics of amodiaquine were investigated in two studies.259, 309 Rijken et al.259

reported no difference in pharmacokinetic parameters between pregnant women with P.vivax malaria (n = 24) and post-partum women (n = 19), except for the maximumconcentration (Cmax) of desethylamodiaquine (DEAQ), the principle metabolite ofamodiaquine, that was significantly lower in pregnant women (p = 0.019). However,because the difference was below 10 % and the total exposure to (desethyl)amodiaquine didnot differ significantly, the clinical impact of this difference was considered limited. Therewas no significant difference in pharmacokinetic parameters between the 2nd and 3rdtrimester of pregnancy. Also, there was no significant pharmacokinetic difference betweenpost-partum women with P. vivax malaria and those without it, making it unlikely that adisease effect masked the differences between pregnant and post-partum women. Pregnantwomen with recurrent P. vivax malaria did have a significantly lower dose-normalizedamodiaquine exposure than post-partum women (p = 0.036), suggesting that high drugexposure suppresses recurrent malaria.

Tarning et al.259 did a compartmental analysis of the same data using a lagged first-orderabsorption with a two-compartment disposition model followed by a three-compartmentdisposition of desethylamodiaquine. They found a relatively small effect of age ofamodiaquine clearance (1.36 % reduction per year), which might be related to an increasedimmunity in older patients and reflect reduced severity of the disease. Also, pregnant patientshad a reduced absorption lag time (41.6 % decrease), possibly as a result of increased cardiacoutput resulting in an increased blood flow to the stomach and small intestine.440 Neitherpregnancy status nor estimated gestational age resulted in a clinically relevant impact onother pharmacokinetic parameters.



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MefloquineThe pharmacokinetics of mefloquine in pregnancy have been investigated initially in the90s, and been re-examined recently.425, 428, 429 Nosten et al.428 investigated thepharmacokinetics in 20 pregnant women who received either 125 of 250 mg of oralmefloquine monotherapy. They compared their outcomes with the literature and found ahigher oral clearance and a shorter terminal elimination half-life in pregnant women. Therewas no evidence of delayed absorption. Mean maximum concentrations of mefloquine inwomen who received 250 mg of AS were significantly lower than previously reported in sixhealthy Brazilian volunteers.441-453

Na Bangchang et al.429 compared nine pregnant women with eight non-pregnant women, allsuffering from uncomplicated falciparum malaria, who received a single-dose treatment ofmefloquine (15 mg/kg). They found a significantly lower maximum concentration of wholeblood mefloquine (p = 0.015) and an increased total apparent volume of distribution(p = 0.046) in the pregnant women. The pregnant women also tended to have increased timesto peak concentration (Tmax) compared to non-pregnant women. However, this differencewas not statistically significant. Systematic clearance and terminal elimination half-life’swere similar in both groups. No correlation between EGA and apparent V/F, t1/2 of CL/Fwere seen.

Valea et al.425 investigated the pharmacokinetic properties of mefloquine in combinationwith AS. They compared the pharmacokinetic parameters of 24 pregnant and 24 non-pregnant women with uncomplicated falciparum malaria, treated with a fixed-dosecombination of oral mefloquine and AS (8/3.6 mg/kg per day for 3 days). They found verysimilar values for Cmax, Tmax and V/F in pregnant and non-pregnant women. However,t1/2 was significantly longer in pregnant women than in non-pregnant women (390.2 vs289.2 h; p < 0.001). Also, pregnant women tended to have longer clearance time and higherexposure to mefloquine, but these differences were not statistically significant. The exposureto carboxymefloquine (an inactive metabolite of mefloquine), however, was lower inpregnant women, consistent with a higher apparent volume of distribution and clearance.These findings suggest that the higher exposure to mefloquine may be a result of decreasedcarboxylation of mefloquine, although the increase in exposure to mefloquine was notcompletely proportional to the decrease in exposure to carboxymefloquine.

Sulfadoxine-pyrimethamineThree studies investigated the pharmacokinetic properties of SP.313, 431, 433 Green et al.433

used a one-compartmental analysis to compare the outcome of 33 pregnant (n = 11:parasitaemic; n = 22: aparasitaemic) and 11 post-partum women without symptomaticmalaria (n = 1: parasitaemic; n = 10: aparasitaemic) treated with the standard single dose SP(1500/75 mg). Linear regression showed a significant effect of parity status on sulfadoxine


129

half-life as well as on exposure (AUC). The half-life of sulfadoxine was significantly shorter(148 vs 256 h; p < 0.0001); exposure (AUC) was significantly lower (22,816 vs40,106 µg/ml/h; p < 0.001); and the plasma clearance rate was significantly higher (65.9 vs36.9 ml/h; p < 0.001) during pregnancy compared with the post-partum period. Pregnancystatus showed no significant effect on the distribution volume. For pyrimethamine, none ofthe pharmacokinetic parameters differed significantly between the pregnant and post-partumwomen, although the median half-life and exposure (AUC) were lower, yet not significantly.

Karunajeewa et al.431 compared the pharmacokinetic properties of SP in 30 pregnant and 30age-matched non-pregnant women who received IPTp (SP 1500/75 mg once andchloroquine 1350 mg q.d. for 3 days). They found a significantly lower exposure (AUC) forsulfadoxine (33 %), for N-acetylsulfadoxine (a metabolite of sulfadoxine) and forpyrimethamine (32 %) in the pregnant group; which is in line with the significantly higherclearance rates for (N-acetyl)sulfadoxine and pyrimethamine found in this study. The totalapparent volume of distribution was significantly higher in pregnant women for (N-acetyl)sulfadoxine and pyrimethamine. The terminal elimination rate of sulfadoxine and N-acetylsulfadoxine was significantly higher in pregnant women, while the terminalelimination rate of pyrimethamine was significantly lower in this group.

Nyunt et al.313 investigated the pharmacokinetics of SP in Intermittent Preventive Treatment(IPTp) of malaria in 98 pregnant and 77 post-partum women from four African countries.Using a one-compartment model, they found significantly higher maximum concentrationsof sulfadoxine in pregnant women, but lower exposure (AUC), faster clearance, smallervolume of distribution and shorter elimination half-life’s during pregnancy, all statisticallysignificant. Day 7 concentrations of sulfadoxine did not differ significantly; however, afteradjusting for potential covariates, they were significantly lower during pregnancy. Day 7concentrations appeared to be lower in the third than in the second trimester, but thisdifference was not statistically significant. For pyrimethamine, drug exposure was higherduring pregnancy, which is consistent with a significantly slower total clearance, longerelimination half-life and an apparently smaller distribution volume during pregnancy. Aswell, the unadjusted day 7 concentration of pyrimethamine was significantly higher inpregnant women. All pharmacokinetic parameters varied significantly between the studysites.

PiperaquineFive articles report the pharmacokinetic properties of PQ. Two studies conducted by Rijkenet al. and Tarning et al. are based on one study of the pharmacokinetics of PQ after the oraladministration of DHA-PPQ (6.4 and 51.2 mg/kg q.d. divided over 3 days).267, 268 Thefindings for DHA are described above. Rijken et al.267 used a non-compartmental analysisto describe the pharmacokinetic properties of PPQ in 24 pregnant and 24 non-pregnant



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MefloquineThe pharmacokinetics of mefloquine in pregnancy have been investigated initially in the90s, and been re-examined recently.425, 428, 429 Nosten et al.428 investigated thepharmacokinetics in 20 pregnant women who received either 125 of 250 mg of oralmefloquine monotherapy. They compared their outcomes with the literature and found ahigher oral clearance and a shorter terminal elimination half-life in pregnant women. Therewas no evidence of delayed absorption. Mean maximum concentrations of mefloquine inwomen who received 250 mg of AS were significantly lower than previously reported in sixhealthy Brazilian volunteers.441-453

Na Bangchang et al.429 compared nine pregnant women with eight non-pregnant women, allsuffering from uncomplicated falciparum malaria, who received a single-dose treatment ofmefloquine (15 mg/kg). They found a significantly lower maximum concentration of wholeblood mefloquine (p = 0.015) and an increased total apparent volume of distribution(p = 0.046) in the pregnant women. The pregnant women also tended to have increased timesto peak concentration (Tmax) compared to non-pregnant women. However, this differencewas not statistically significant. Systematic clearance and terminal elimination half-life’swere similar in both groups. No correlation between EGA and apparent V/F, t1/2 of CL/Fwere seen.

Valea et al.425 investigated the pharmacokinetic properties of mefloquine in combinationwith AS. They compared the pharmacokinetic parameters of 24 pregnant and 24 non-pregnant women with uncomplicated falciparum malaria, treated with a fixed-dosecombination of oral mefloquine and AS (8/3.6 mg/kg per day for 3 days). They found verysimilar values for Cmax, Tmax and V/F in pregnant and non-pregnant women. However,t1/2 was significantly longer in pregnant women than in non-pregnant women (390.2 vs289.2 h; p < 0.001). Also, pregnant women tended to have longer clearance time and higherexposure to mefloquine, but these differences were not statistically significant. The exposureto carboxymefloquine (an inactive metabolite of mefloquine), however, was lower inpregnant women, consistent with a higher apparent volume of distribution and clearance.These findings suggest that the higher exposure to mefloquine may be a result of decreasedcarboxylation of mefloquine, although the increase in exposure to mefloquine was notcompletely proportional to the decrease in exposure to carboxymefloquine.

Sulfadoxine-pyrimethamineThree studies investigated the pharmacokinetic properties of SP.313, 431, 433 Green et al.433

used a one-compartmental analysis to compare the outcome of 33 pregnant (n = 11:parasitaemic; n = 22: aparasitaemic) and 11 post-partum women without symptomaticmalaria (n = 1: parasitaemic; n = 10: aparasitaemic) treated with the standard single dose SP(1500/75 mg). Linear regression showed a significant effect of parity status on sulfadoxine


129

half-life as well as on exposure (AUC). The half-life of sulfadoxine was significantly shorter(148 vs 256 h; p < 0.0001); exposure (AUC) was significantly lower (22,816 vs40,106 µg/ml/h; p < 0.001); and the plasma clearance rate was significantly higher (65.9 vs36.9 ml/h; p < 0.001) during pregnancy compared with the post-partum period. Pregnancystatus showed no significant effect on the distribution volume. For pyrimethamine, none ofthe pharmacokinetic parameters differed significantly between the pregnant and post-partumwomen, although the median half-life and exposure (AUC) were lower, yet not significantly.

Karunajeewa et al.431 compared the pharmacokinetic properties of SP in 30 pregnant and 30age-matched non-pregnant women who received IPTp (SP 1500/75 mg once andchloroquine 1350 mg q.d. for 3 days). They found a significantly lower exposure (AUC) forsulfadoxine (33 %), for N-acetylsulfadoxine (a metabolite of sulfadoxine) and forpyrimethamine (32 %) in the pregnant group; which is in line with the significantly higherclearance rates for (N-acetyl)sulfadoxine and pyrimethamine found in this study. The totalapparent volume of distribution was significantly higher in pregnant women for (N-acetyl)sulfadoxine and pyrimethamine. The terminal elimination rate of sulfadoxine and N-acetylsulfadoxine was significantly higher in pregnant women, while the terminalelimination rate of pyrimethamine was significantly lower in this group.

Nyunt et al.313 investigated the pharmacokinetics of SP in Intermittent Preventive Treatment(IPTp) of malaria in 98 pregnant and 77 post-partum women from four African countries.Using a one-compartment model, they found significantly higher maximum concentrationsof sulfadoxine in pregnant women, but lower exposure (AUC), faster clearance, smallervolume of distribution and shorter elimination half-life’s during pregnancy, all statisticallysignificant. Day 7 concentrations of sulfadoxine did not differ significantly; however, afteradjusting for potential covariates, they were significantly lower during pregnancy. Day 7concentrations appeared to be lower in the third than in the second trimester, but thisdifference was not statistically significant. For pyrimethamine, drug exposure was higherduring pregnancy, which is consistent with a significantly slower total clearance, longerelimination half-life and an apparently smaller distribution volume during pregnancy. Aswell, the unadjusted day 7 concentration of pyrimethamine was significantly higher inpregnant women. All pharmacokinetic parameters varied significantly between the studysites.

PiperaquineFive articles report the pharmacokinetic properties of PQ. Two studies conducted by Rijkenet al. and Tarning et al. are based on one study of the pharmacokinetics of PQ after the oraladministration of DHA-PPQ (6.4 and 51.2 mg/kg q.d. divided over 3 days).267, 268 Thefindings for DHA are described above. Rijken et al.267 used a non-compartmental analysisto describe the pharmacokinetic properties of PPQ in 24 pregnant and 24 non-pregnant



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women with falciparum malaria. They found no significant difference in total PPQ exposurebetween the pregnant and non-pregnant women. However, the exposure in the first 72 h(AUC0-24 h; AUC24-48 h and AUC48-72 h) was significantly higher in the pregnantwomen; as well, the day 7 concentration was significantly elevated. The apparent volume ofdistribution was significantly smaller (602 vs 877 L/kg; p = 0.0057) and the terminalelimination half-life was significantly shorter (17.8 vs 25.6 days; p = 0.0023) in the pregnantgroup. No statistically significant difference was found in clearance rate. The Cmax waselevated after each dose, but only significantly after the first two doses.

Tarning et al.268 did a compartmental analysis with the same data, using a three-compartmentdisposition model with a 45 % higher elimination clearance and a 47 % increase in relativebioavailability in pregnant women compared with non-pregnant women. They found noeffect of pregnancy on exposure of PPQ. However, the terminal elimination half-life wasshorter (17.5 vs 24.0 days; p < 0.001), the apparent volume of distribution lower (529 vs829 L/kg; p < 0.001) and the maximum concentration higher (291 vs 216 ng/ml; p = 0.035)in the pregnant women. The time to maximum concentration, clearance rate and day 7 and28 concentration did not differ significantly between the two groups.

Adam et al.311 reported a significantly higher exposure (AUC0-24; 1.8 vs 0.86 µg h/ml;p = 0.01) and a longer time to maximum concentration (Tmax; 4.00 vs 1.50; p = 0.02) afterthe first dose of DHA-PPQ (24/20 mg/kg q.d. for 3 days) in 12 pregnant women comparedto 12 non-pregnant women with uncomplicated falciparum malaria. No other significantdifferences were observed, including no difference in total exposure (AUC0-∞). Thatnotwithstanding, there was a trend towards higher maximum concentrations of PPQ and ashorter half-life in pregnant women, compared to non-pregnant women.

A compartmental analysis using a three-compartment disposition model with a transit-absorption model of the same data was performed by Hoglund et al.432 They found asignificantly higher maximum concentration (Cmax; 185 vs 102 ng/ml; p = 0.021) and longertime to maximum concentration (Tmax; 30.7 vs 1.48 h; p = 0.018) in the 12 pregnant womencompared to the 12 non-pregnant women. The terminal elimination half-life was shorter inthe pregnant group (t1/2; 22.1 vs 25.7 days; p = 0.001). However, no significant differencesin exposure to PPQ and day 7 and 28 concentrations were observed.

Benjamin et al.434 reported a 33 % lower exposure (AUC; 23.721 vs 35.644 µg h/L;p < 0.001) in pregnant women compared to non-pregnant women, consistent with asignificantly shorter half-life (t1/2; 382 vs 488 h; p < 0.001) and a higher clearance rate(CL/F; 73.5 vs 53.8 L/h; p < 0.001).


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Atovaquone-proguanil (AP)The pharmacokinetic properties of proguanil (PG) were first studied in 1993 byWangboonskul et al.424 The pharmacokinetic parameters of PG (pro-drug), cycloguanil (CG)(active metabolite) and 4-chlorophenylbiguanide (inactive metabolite) were compared in 10healthy pregnant women, four post-partum women and nine male patients; all treated withPG (200 mg p.o. once).454 They found a significantly lower maximum concentration of CGin pregnant women (Cmax; 12.5 vs 28.4 (post-partum) and 39.3 (male) ng/ml; p < 0.05) anda significantly shorter terminal elimination half-life for PG (t1/2; 12.3 vs 17.1 (post-partum)and 16.1 (male) h; p < 0.01) in the pregnant group. The total exposure (AUC) of CG inpregnant women was approximately half of the exposure in male and post-partum patients.The mean ratio of the exposure of PG to CG was 18.0 in pregnancy, compared to 7.8 post-partum. The 4-chlorophenylbiguanide maximum concentration was lower in the pregnantwomen than in the post-partum and male patients, but not significantly. All theseobservations seemed to indicate an impaired conversion of pro-drug to (active) metabolite.

McGready et al.256 investigated the pharmacokinetic properties of AS-AP (4/20/8 mg/kg p.o.q.d. for 3 days) in 24 pregnant patients with recrudescent multi-drug resistant uncomplicatedmalaria. A noncompartmental and compartmental analysis was performed. For atovaquone,PG and CG, they found a lower (corrected) maximum concentration (Cmax) and totalexposure (AUC) in pregnant women compared with healthy volunteers from the samepopulation455 and compared with Thai children with malaria.456 The terminal eliminationhalf-life of atovaquone was significantly longer in the pregnant women. The non-compartmental analysis for PG showed 40 % lower maximum concentrations (Cmax) andexposure (AUC) in pregnant women with acute malaria than in non-pregnant healthy adults.The lower PG concentrations were attributed in the population pharmacokinetic assessmentto increased apparent volume of distribution and clearance rate.

Another study by McGready et al.430 investigated the influences of pregnancy onbiotransformation of PG to CG. They found similar PG plasma concentrations 6 h afteradministration of a single dose of PG (200 mg p.o.) in 45 women during pregnancy and thesame 45 women at least two months post partum. Plasma concentrations (corrected for dose)of CG 6 h after administration of PG were significantly lower during pregnancy than postpartum (25.0 vs 37.4 ng/ml; p < 0.01). The ratio of plasma and urine PG and CGconcentrations increased significantly in pregnancy. The urine concentration of PG and CGwere significantly higher during pregnancy.

Na Bangchang et al.317 studied the pharmacokinetics of atovaquone and PG in pregnantwomen from Thailand (n = 8) and Zambia (n = 18) treated with AP (1000/400 mg p.o. q.d.for 3 days) for uncomplicated falciparum malaria. They found no significant differences inany of the pharmacokinetic parameters of atovaquone, PG or CG between patients from



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women with falciparum malaria. They found no significant difference in total PPQ exposurebetween the pregnant and non-pregnant women. However, the exposure in the first 72 h(AUC0-24 h; AUC24-48 h and AUC48-72 h) was significantly higher in the pregnantwomen; as well, the day 7 concentration was significantly elevated. The apparent volume ofdistribution was significantly smaller (602 vs 877 L/kg; p = 0.0057) and the terminalelimination half-life was significantly shorter (17.8 vs 25.6 days; p = 0.0023) in the pregnantgroup. No statistically significant difference was found in clearance rate. The Cmax waselevated after each dose, but only significantly after the first two doses.

Tarning et al.268 did a compartmental analysis with the same data, using a three-compartmentdisposition model with a 45 % higher elimination clearance and a 47 % increase in relativebioavailability in pregnant women compared with non-pregnant women. They found noeffect of pregnancy on exposure of PPQ. However, the terminal elimination half-life wasshorter (17.5 vs 24.0 days; p < 0.001), the apparent volume of distribution lower (529 vs829 L/kg; p < 0.001) and the maximum concentration higher (291 vs 216 ng/ml; p = 0.035)in the pregnant women. The time to maximum concentration, clearance rate and day 7 and28 concentration did not differ significantly between the two groups.

Adam et al.311 reported a significantly higher exposure (AUC0-24; 1.8 vs 0.86 µg h/ml;p = 0.01) and a longer time to maximum concentration (Tmax; 4.00 vs 1.50; p = 0.02) afterthe first dose of DHA-PPQ (24/20 mg/kg q.d. for 3 days) in 12 pregnant women comparedto 12 non-pregnant women with uncomplicated falciparum malaria. No other significantdifferences were observed, including no difference in total exposure (AUC0-∞). Thatnotwithstanding, there was a trend towards higher maximum concentrations of PPQ and ashorter half-life in pregnant women, compared to non-pregnant women.

A compartmental analysis using a three-compartment disposition model with a transit-absorption model of the same data was performed by Hoglund et al.432 They found asignificantly higher maximum concentration (Cmax; 185 vs 102 ng/ml; p = 0.021) and longertime to maximum concentration (Tmax; 30.7 vs 1.48 h; p = 0.018) in the 12 pregnant womencompared to the 12 non-pregnant women. The terminal elimination half-life was shorter inthe pregnant group (t1/2; 22.1 vs 25.7 days; p = 0.001). However, no significant differencesin exposure to PPQ and day 7 and 28 concentrations were observed.

Benjamin et al.434 reported a 33 % lower exposure (AUC; 23.721 vs 35.644 µg h/L;p < 0.001) in pregnant women compared to non-pregnant women, consistent with asignificantly shorter half-life (t1/2; 382 vs 488 h; p < 0.001) and a higher clearance rate(CL/F; 73.5 vs 53.8 L/h; p < 0.001).


131

Atovaquone-proguanil (AP)The pharmacokinetic properties of proguanil (PG) were first studied in 1993 byWangboonskul et al.424 The pharmacokinetic parameters of PG (pro-drug), cycloguanil (CG)(active metabolite) and 4-chlorophenylbiguanide (inactive metabolite) were compared in 10healthy pregnant women, four post-partum women and nine male patients; all treated withPG (200 mg p.o. once).454 They found a significantly lower maximum concentration of CGin pregnant women (Cmax; 12.5 vs 28.4 (post-partum) and 39.3 (male) ng/ml; p < 0.05) anda significantly shorter terminal elimination half-life for PG (t1/2; 12.3 vs 17.1 (post-partum)and 16.1 (male) h; p < 0.01) in the pregnant group. The total exposure (AUC) of CG inpregnant women was approximately half of the exposure in male and post-partum patients.The mean ratio of the exposure of PG to CG was 18.0 in pregnancy, compared to 7.8 post-partum. The 4-chlorophenylbiguanide maximum concentration was lower in the pregnantwomen than in the post-partum and male patients, but not significantly. All theseobservations seemed to indicate an impaired conversion of pro-drug to (active) metabolite.

McGready et al.256 investigated the pharmacokinetic properties of AS-AP (4/20/8 mg/kg p.o.q.d. for 3 days) in 24 pregnant patients with recrudescent multi-drug resistant uncomplicatedmalaria. A noncompartmental and compartmental analysis was performed. For atovaquone,PG and CG, they found a lower (corrected) maximum concentration (Cmax) and totalexposure (AUC) in pregnant women compared with healthy volunteers from the samepopulation455 and compared with Thai children with malaria.456 The terminal eliminationhalf-life of atovaquone was significantly longer in the pregnant women. The non-compartmental analysis for PG showed 40 % lower maximum concentrations (Cmax) andexposure (AUC) in pregnant women with acute malaria than in non-pregnant healthy adults.The lower PG concentrations were attributed in the population pharmacokinetic assessmentto increased apparent volume of distribution and clearance rate.

Another study by McGready et al.430 investigated the influences of pregnancy onbiotransformation of PG to CG. They found similar PG plasma concentrations 6 h afteradministration of a single dose of PG (200 mg p.o.) in 45 women during pregnancy and thesame 45 women at least two months post partum. Plasma concentrations (corrected for dose)of CG 6 h after administration of PG were significantly lower during pregnancy than postpartum (25.0 vs 37.4 ng/ml; p < 0.01). The ratio of plasma and urine PG and CGconcentrations increased significantly in pregnancy. The urine concentration of PG and CGwere significantly higher during pregnancy.

Na Bangchang et al.317 studied the pharmacokinetics of atovaquone and PG in pregnantwomen from Thailand (n = 8) and Zambia (n = 18) treated with AP (1000/400 mg p.o. q.d.for 3 days) for uncomplicated falciparum malaria. They found no significant differences inany of the pharmacokinetic parameters of atovaquone, PG or CG between patients from



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Thailand and Zambia. Atovaquone was slowly absorbed and slowly eliminated withconsiderable variation among individuals. The maximum concentration (Cmax) and exposure(AUC) of atovaquone found in this study were approximately half of those found in otherstudies in healthy volunteers and Thai children with malaria.456, 457 No significant differenceswere seen in the pharmacokinetics of PG. Both the maximum concentration (Cmax) andexposure (AUC) of CG were considerably lower in this study compared to other studies.456-

458

Discussion

This systematic review synthesized and compiled data on ACT pharmacokinetics anddynamics during pregnancy, and the consequences thereof on treatment dose and regime.The previous systematic review on this subject was published in 2009.421 The present reviewencompasses 27 reports with a total of 829 pregnant and 377 non-pregnant women.241, 248,

251, 253, 256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-433 The number of trials that were found are ratherlimited and disproportional low in view of to the large number of pregnant women withmalaria infections worldwide. This has several reasons, first of all, pregnant women aresystematically excluded from clinical trials (because of the risk of the unborn child to beexposed to harmful effects). Furthermore, there is a limited research funding available fortrials, especially pharmacokinetic studies. Funding organizations prefer phase III orrandomized clinical trials over pharmacokinetic studies. The identified studies also differedin quality (see Additional file 3). However, in general, study quality was moderate to good,and the evidence is strong enough to draw conclusions regarding pharmacokinetic changesthat are exhibited in pregnant women. Although current WHO guidelines stronglyrecommend to treat malaria in the first trimester with quinine (combined with clindamycine),these will not be discussed in this review which is focussed on ACT.

Artemether, artesunate and dihydroartemisininArtemisinin-based compounds have been investigated in good quality studies. Two studieson the pharmacokinetic properties of artemether and its principle metabolite DHA suggestthat the maximum concentration (Cmax) and exposure (AUC) of artemether and DHAfollowing treatment with oral AL are lower in pregnant women than in non-pregnantpatients. It also showed that there is no significant difference between the second and thirdtrimester of pregnancy.251, 258 However, since there has been no direct comparative trial,these results should be interpreted with caution. A larger sample size comparative trialshould be conducted to statistically confirm or rule out any clinically important effect ofpregnancy on pharmacokinetic parameters.

Although the outcome of the studies on the pharmacokinetic properties of AS seemconflicting, they provide substantial evidence that pregnancy induces clearance and thus


133

leads to lower exposure to AS and DHA. While three studies found a higher DHAexposure241 or no significant differences in DHA pharmacokinetics between the twogroups,425, 427 other studies provided enough evidence to explain this apparent contradictionby the independent and opposite effect of malaria infection on pharmacokineticproperties.251, 312, 427, 436 The higher bioavailability and exposure resulting from malarialinfection in thought to have masked the pregnancy related effects on pharmacokinetics. Thisconclusion is worrying as pregnant women might be at risk of under dosing, resulting inlower cure rates and a more rapid development of resistance to DHA, and urgently calls forreassessment of the treatment dose of artesunate. The exact mechanisms are unfortunatelycurrently unknown. A dose optimization study will be necessary to find the ideal dose ofartesunate-containing ACT in pregnancy in order to augment clinical efficacy and ensuresafety.

Pharmacokinetic properties after administration of oral DHA were investigated in twostudies. A non-compartmental analysis of the data of the first study showed a trend of lowerexposure. However, the differences were only statistically significant after the first dose,possibly because of small sample sizes and high inter-individual variability. Thecompartmental analysis of the same data showed 38 % lower total exposure and significantlyhigher clearance rates and apparent volume of distribution. The second study reported nodifferences in pharmacokinetic properties between pregnant and non-pregnant women. Ofinterest, the first study included women with falciparum malaria, while the parasitaemic rateof the participants was very low in the second study. Further studies with larger sample sizesof the effect of pregnancy on DHA pharmacokinetics are recommended.

LumefantrineAn important development in the past 5 years are that several controlled studies werepublished on lumefantrine. Studies investigating the pharmacokinetic properties oflumefantrine show a low day 7 concentration and large proportions of concentrations belowvalues that are associated with high failure rates.248, 251, 253, 315, 426, 438 One study also showeda significantly lower lumefantrine exposure in pregnant women,251 while another studyshowed significantly shorter Tmaxand T1/2, but no statistically significant differences inlumefantrine exposure.426 Especially the lower day 7 concentrations are reason for concernand ask for more extensive research and reconsideration of the drug dose. Future studiesshould investigate whether drug exposure improves with a standard six-dose regimen oflumefantrine given over 5 days compared to the standard regimen of 3 days. Important tonote is that still much remains unknown regarding the variable absorption of lumefantrine(which is a lipophilic compound) in the digestive tract affecting pharmacokinetic values. Inthe included trials in this review, the absorption of lumefantrine was maximized by providingfatty foods (e.g. milk). However, in daily clinical practice in endemic countries, it iscompletely unknown which percentage of (pregnant) women co-administer high-fat foods.



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Thailand and Zambia. Atovaquone was slowly absorbed and slowly eliminated withconsiderable variation among individuals. The maximum concentration (Cmax) and exposure(AUC) of atovaquone found in this study were approximately half of those found in otherstudies in healthy volunteers and Thai children with malaria.456, 457 No significant differenceswere seen in the pharmacokinetics of PG. Both the maximum concentration (Cmax) andexposure (AUC) of CG were considerably lower in this study compared to other studies.456-

458

Discussion

This systematic review synthesized and compiled data on ACT pharmacokinetics anddynamics during pregnancy, and the consequences thereof on treatment dose and regime.The previous systematic review on this subject was published in 2009.421 The present reviewencompasses 27 reports with a total of 829 pregnant and 377 non-pregnant women.241, 248,

251, 253, 256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-433 The number of trials that were found are ratherlimited and disproportional low in view of to the large number of pregnant women withmalaria infections worldwide. This has several reasons, first of all, pregnant women aresystematically excluded from clinical trials (because of the risk of the unborn child to beexposed to harmful effects). Furthermore, there is a limited research funding available fortrials, especially pharmacokinetic studies. Funding organizations prefer phase III orrandomized clinical trials over pharmacokinetic studies. The identified studies also differedin quality (see Additional file 3). However, in general, study quality was moderate to good,and the evidence is strong enough to draw conclusions regarding pharmacokinetic changesthat are exhibited in pregnant women. Although current WHO guidelines stronglyrecommend to treat malaria in the first trimester with quinine (combined with clindamycine),these will not be discussed in this review which is focussed on ACT.

Artemether, artesunate and dihydroartemisininArtemisinin-based compounds have been investigated in good quality studies. Two studieson the pharmacokinetic properties of artemether and its principle metabolite DHA suggestthat the maximum concentration (Cmax) and exposure (AUC) of artemether and DHAfollowing treatment with oral AL are lower in pregnant women than in non-pregnantpatients. It also showed that there is no significant difference between the second and thirdtrimester of pregnancy.251, 258 However, since there has been no direct comparative trial,these results should be interpreted with caution. A larger sample size comparative trialshould be conducted to statistically confirm or rule out any clinically important effect ofpregnancy on pharmacokinetic parameters.

Although the outcome of the studies on the pharmacokinetic properties of AS seemconflicting, they provide substantial evidence that pregnancy induces clearance and thus


133

leads to lower exposure to AS and DHA. While three studies found a higher DHAexposure241 or no significant differences in DHA pharmacokinetics between the twogroups,425, 427 other studies provided enough evidence to explain this apparent contradictionby the independent and opposite effect of malaria infection on pharmacokineticproperties.251, 312, 427, 436 The higher bioavailability and exposure resulting from malarialinfection in thought to have masked the pregnancy related effects on pharmacokinetics. Thisconclusion is worrying as pregnant women might be at risk of under dosing, resulting inlower cure rates and a more rapid development of resistance to DHA, and urgently calls forreassessment of the treatment dose of artesunate. The exact mechanisms are unfortunatelycurrently unknown. A dose optimization study will be necessary to find the ideal dose ofartesunate-containing ACT in pregnancy in order to augment clinical efficacy and ensuresafety.

Pharmacokinetic properties after administration of oral DHA were investigated in twostudies. A non-compartmental analysis of the data of the first study showed a trend of lowerexposure. However, the differences were only statistically significant after the first dose,possibly because of small sample sizes and high inter-individual variability. Thecompartmental analysis of the same data showed 38 % lower total exposure and significantlyhigher clearance rates and apparent volume of distribution. The second study reported nodifferences in pharmacokinetic properties between pregnant and non-pregnant women. Ofinterest, the first study included women with falciparum malaria, while the parasitaemic rateof the participants was very low in the second study. Further studies with larger sample sizesof the effect of pregnancy on DHA pharmacokinetics are recommended.

LumefantrineAn important development in the past 5 years are that several controlled studies werepublished on lumefantrine. Studies investigating the pharmacokinetic properties oflumefantrine show a low day 7 concentration and large proportions of concentrations belowvalues that are associated with high failure rates.248, 251, 253, 315, 426, 438 One study also showeda significantly lower lumefantrine exposure in pregnant women,251 while another studyshowed significantly shorter Tmaxand T1/2, but no statistically significant differences inlumefantrine exposure.426 Especially the lower day 7 concentrations are reason for concernand ask for more extensive research and reconsideration of the drug dose. Future studiesshould investigate whether drug exposure improves with a standard six-dose regimen oflumefantrine given over 5 days compared to the standard regimen of 3 days. Important tonote is that still much remains unknown regarding the variable absorption of lumefantrine(which is a lipophilic compound) in the digestive tract affecting pharmacokinetic values. Inthe included trials in this review, the absorption of lumefantrine was maximized by providingfatty foods (e.g. milk). However, in daily clinical practice in endemic countries, it iscompletely unknown which percentage of (pregnant) women co-administer high-fat foods.



Chapter 5

134

AmodiaquineThe reported studies with oral amodiaquine for the treatment of vivax malaria in Thailandrevealed no clinically relevant differences in pharmacokinetic parameters between pregnantand post-partum women. There was no significant difference between post-partum womenwith malaria and without malaria, making it unlikely that a disease effect masked possibledifferences. Therefore, no dosage adjustments are recommended.

MefloquineTwo studies dating from 1990 and 1994 report significantly lower maximum concentrationsof mefloquine in pregnant women compared to healthy Brazilian volunteers428, 441 and non-pregnant women.429 In contrast to a recent study that showed similar values for Cmax inpregnant and non-pregnant women with falciparum malaria and a non-significant trendtowards longer clearance and higher exposure to mefloquine. In the first two studies, patientsreceived one dose of oral AS in a low dose as prophylaxis428 or in a higher dose as treatmentfor chloroquine-resistant falciparum malaria,429 while in the recent study a 3 days course oftreatment of given.425 These differences in drug regimes, besides other variables, might havean influence on the pharmacokinetic parameters. It was thought that altered plasmaconcentrations of mefloquine were caused by the increased volume of distribution. Theresults of the most recent trial425 suggests that although the exposure was higher, thecarboxymefloquine concentration was reduced (with simultaneous increase in V/F andremoval of the metabolite). The reduced carboxylation might be partially responsible for theof the compound in pregnant women. Larger trials with comparative drug regimens,metabolite profiles and compartmental analysis and patient groups would thus be necessaryto draw strong conclusions on the effect of pregnancy on the pharmacokinetic properties ofmefloquine.

Sulfadoxine-pyrimethamineThe reported studies with SP (used for IPTp) all show a significant lower exposure, higherclearance rates and shorter terminal half-life of sulfadoxine in pregnant women comparedwith post-partum women.313, 431, 433 This suggests that higher doses of sulfadoxine would bebeneficial for the efficacy of IPTp even when the parasites are fully susceptible to sulfa drugcombinations.

No general conclusion can be drawn for the pyrimethamine pharmacokinetics, since a studyin Kenya showed no differences in pharmacokinetic parameters between pregnant and post-partum women,433 while a study in Papua New Guinea (PNG) reported significantly lowerexposure and higher clearance rates.431 A study in four African countries describedsignificantly higher exposure and lower clearance rates in pregnant women. Possibleexplanations could be the different rates of parasitaemia between the studies (0–43 %) and


135

the concurrent administration of chloroquine in the study in PNG. Further (observational orinterventional) research will be necessary to assess the influence of pregnancy on thepharmacokinetic properties of pyrimethamine. However, with resistance hampering its use,the prospects for an extended PK evaluation of sulfa drug combinations used for IPTp appearto be limited.459 The search for suitable alternative drug (combinations) for IPTp isongoing.460

PiperaquineThe reported studies suggest an influence of pregnancy on the pharmacokinetic propertiesof PQ. Four of the five studies show either an elevated exposure after the first dose,267, 311 a(significantly) higher Cmax and shorter terminal elimination half-lifes.267, 268, 311, 432 However,none of the studies showed a significantly higher total exposure, probably limiting theclinical consequences of the influence of pregnancy. Thereby, one study reported asignificantly lower exposure in the pregnant group, a shorter half-life and a higher apparentvolume of distribution. These discrepancies emphasize the need for further research.

AtovaquoneThe studies investigating atovaquone pharmacokinetics show a more than 50 % lowerCmax and total exposure in pregnant women with falciparum malaria compared to healthyvolunteers.256, 317 Although these results should be interpreted with caution due to smallsample sizes, higher dosing of atovaquone ought to be considered.

ProguanilThe pharmacokinetic parameters of PG did not differ significantly in most studies, but themaximum concentration and terminal elimination half-life of the active metabolite of PG,CG, were significantly lower and shorter in pregnant women. Also, the PG–CG-ratio wassignificantly elevated in two studies, suggesting an impaired conversion of PG to CG. SinceCG is mainly responsible for the therapeutic effect of PG, this might compromise theefficacy; and as well, the dose of the PG portion in the AP combination may have to be re-considered.

Limitations

This systematic review is subject to several limitations. First, there is a considerable degreeof heterogeneity in the outcomes and parameters that were reported in the articles. Forexample, time intervals for exposure differed significantly between the studies; which makesit more difficult to compare the outcomes of different studies. Also, different units andmethods of measurement for the outcomes were used in different studies, complicating directcomparisons. Secondly, there was a large heterogeneity in the control groups. In some



5

Chapter 5

134

AmodiaquineThe reported studies with oral amodiaquine for the treatment of vivax malaria in Thailandrevealed no clinically relevant differences in pharmacokinetic parameters between pregnantand post-partum women. There was no significant difference between post-partum womenwith malaria and without malaria, making it unlikely that a disease effect masked possibledifferences. Therefore, no dosage adjustments are recommended.

MefloquineTwo studies dating from 1990 and 1994 report significantly lower maximum concentrationsof mefloquine in pregnant women compared to healthy Brazilian volunteers428, 441 and non-pregnant women.429 In contrast to a recent study that showed similar values for Cmax inpregnant and non-pregnant women with falciparum malaria and a non-significant trendtowards longer clearance and higher exposure to mefloquine. In the first two studies, patientsreceived one dose of oral AS in a low dose as prophylaxis428 or in a higher dose as treatmentfor chloroquine-resistant falciparum malaria,429 while in the recent study a 3 days course oftreatment of given.425 These differences in drug regimes, besides other variables, might havean influence on the pharmacokinetic parameters. It was thought that altered plasmaconcentrations of mefloquine were caused by the increased volume of distribution. Theresults of the most recent trial425 suggests that although the exposure was higher, thecarboxymefloquine concentration was reduced (with simultaneous increase in V/F andremoval of the metabolite). The reduced carboxylation might be partially responsible for theof the compound in pregnant women. Larger trials with comparative drug regimens,metabolite profiles and compartmental analysis and patient groups would thus be necessaryto draw strong conclusions on the effect of pregnancy on the pharmacokinetic properties ofmefloquine.

Sulfadoxine-pyrimethamineThe reported studies with SP (used for IPTp) all show a significant lower exposure, higherclearance rates and shorter terminal half-life of sulfadoxine in pregnant women comparedwith post-partum women.313, 431, 433 This suggests that higher doses of sulfadoxine would bebeneficial for the efficacy of IPTp even when the parasites are fully susceptible to sulfa drugcombinations.

No general conclusion can be drawn for the pyrimethamine pharmacokinetics, since a studyin Kenya showed no differences in pharmacokinetic parameters between pregnant and post-partum women,433 while a study in Papua New Guinea (PNG) reported significantly lowerexposure and higher clearance rates.431 A study in four African countries describedsignificantly higher exposure and lower clearance rates in pregnant women. Possibleexplanations could be the different rates of parasitaemia between the studies (0–43 %) and


135

the concurrent administration of chloroquine in the study in PNG. Further (observational orinterventional) research will be necessary to assess the influence of pregnancy on thepharmacokinetic properties of pyrimethamine. However, with resistance hampering its use,the prospects for an extended PK evaluation of sulfa drug combinations used for IPTp appearto be limited.459 The search for suitable alternative drug (combinations) for IPTp isongoing.460

PiperaquineThe reported studies suggest an influence of pregnancy on the pharmacokinetic propertiesof PQ. Four of the five studies show either an elevated exposure after the first dose,267, 311 a(significantly) higher Cmax and shorter terminal elimination half-lifes.267, 268, 311, 432 However,none of the studies showed a significantly higher total exposure, probably limiting theclinical consequences of the influence of pregnancy. Thereby, one study reported asignificantly lower exposure in the pregnant group, a shorter half-life and a higher apparentvolume of distribution. These discrepancies emphasize the need for further research.

AtovaquoneThe studies investigating atovaquone pharmacokinetics show a more than 50 % lowerCmax and total exposure in pregnant women with falciparum malaria compared to healthyvolunteers.256, 317 Although these results should be interpreted with caution due to smallsample sizes, higher dosing of atovaquone ought to be considered.

ProguanilThe pharmacokinetic parameters of PG did not differ significantly in most studies, but themaximum concentration and terminal elimination half-life of the active metabolite of PG,CG, were significantly lower and shorter in pregnant women. Also, the PG–CG-ratio wassignificantly elevated in two studies, suggesting an impaired conversion of PG to CG. SinceCG is mainly responsible for the therapeutic effect of PG, this might compromise theefficacy; and as well, the dose of the PG portion in the AP combination may have to be re-considered.

Limitations

This systematic review is subject to several limitations. First, there is a considerable degreeof heterogeneity in the outcomes and parameters that were reported in the articles. Forexample, time intervals for exposure differed significantly between the studies; which makesit more difficult to compare the outcomes of different studies. Also, different units andmethods of measurement for the outcomes were used in different studies, complicating directcomparisons. Secondly, there was a large heterogeneity in the control groups. In some



Chapter 5

136

studies, the pregnant women acted as their own post-partum controls, with or without(symptomatic) malaria, while in other studies non-pregnant women or men were used, alsowith or without (symptomatic) malaria. In some studies no control group was available, sodata were compared with literature values. There was a large heterogeneity between thepregnant women, especially regarding parasite density and gestational age estimates.Furthermore, the pharmacokinetic sampling schemes differed among studies, which mighthave had an effect on the outcome parameters. Last, the relatively small sample sizes of allstudies made it difficult to statistically confirm differences in pharmacokinetic properties.For these reasons, a meta-analysis could unfortunately not be conducted.

Conclusion

This systematic review suggests that reassessment of the dose of some components of ACTis necessary to ensure the highest possible efficacy of malaria treatment in pregnant women.Especially for artesunate, lumefantrine, sulfadoxine, atovaquone and proguanil evidencesuggest that with current regimes, pregnant women are under-dosed. Evidence also indicatesthat the effect of pregnancy on amodiaquine and piperaquine is clinically not relevant anddose thus does not have to be changed. For artemether, dihydroartemisinin, lumefantrine,mefloquine and pyrimethamine more extensive research with larger sample sizes is neededto draw strong conclusions on the effect of pregnancy on the pharmacokinetic parameters ofthese components of ACT. Novel approaches such as sampling methods using lower bloodvolumes and minimal preparation (e.g. dried blood spots, high sensitive drug assays), andpopulation pharmacokinetics analysis that are able to investigate the effect of variables suchas age, pregnancy, simultaneously administered drugs, can generate solid data that caninform treatment of malaria in pregnancy.461

Electronic supplementary material

Additional file 1. Methods section. This additional file describes the full methods and searchstrategy.

Additional file 2. Ongoing trials. This additional file summarized ongoing clinical trials onthe subject.

Additional file 3. Quality of included studies. This additional file shows the results of thequality assessment of the individual included studies.

Additional file 4. Data sheet. This additional file shows the original data as extracted fromthe included studies.

Tab

le 1

.Ove

rvie

w a

nd su

mm

ary

of in

clud

ed st

udie

s

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Ben

jam

in(2

015)

Papu

a N

ewG

uine

e (n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

4wks

)an

d ag

e-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

with

mal

aria

infe

ctio

n.

Gro

up 1

DH

A-P

PQ(7

/58

mg/

kgp.

o. q

.d. f

or3

days

)

Gro

up 2

PPQ

(128

0mg

p.o.

q.d

. for

3 da

ys) +

SP

(25m

g/kg

once

)

32 p

regn

ant

wom

en33

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

MTT

, NN

,C

L/F,

Vc/

F,Q

/F, V

p/F,

t 1/2,

AU

C0-

∞.

Klo

prog

ge(2

015)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)w

ithou

t mal

aria

.

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te(4

mg/

kg)

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen Gro

up 2

: 10

wom

en14

pos

tpar

tum

Com

partm

ent

al a

naly

sis

AU

C0-

12,

Cm

ax, T

max

,t 1/

2, C

L/F,

Vd/

F.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

McG

read

y(2

012)

.



5

Chapter 5

136

studies, the pregnant women acted as their own post-partum controls, with or without(symptomatic) malaria, while in other studies non-pregnant women or men were used, alsowith or without (symptomatic) malaria. In some studies no control group was available, sodata were compared with literature values. There was a large heterogeneity between thepregnant women, especially regarding parasite density and gestational age estimates.Furthermore, the pharmacokinetic sampling schemes differed among studies, which mighthave had an effect on the outcome parameters. Last, the relatively small sample sizes of allstudies made it difficult to statistically confirm differences in pharmacokinetic properties.For these reasons, a meta-analysis could unfortunately not be conducted.

Conclusion

This systematic review suggests that reassessment of the dose of some components of ACTis necessary to ensure the highest possible efficacy of malaria treatment in pregnant women.Especially for artesunate, lumefantrine, sulfadoxine, atovaquone and proguanil evidencesuggest that with current regimes, pregnant women are under-dosed. Evidence also indicatesthat the effect of pregnancy on amodiaquine and piperaquine is clinically not relevant anddose thus does not have to be changed. For artemether, dihydroartemisinin, lumefantrine,mefloquine and pyrimethamine more extensive research with larger sample sizes is neededto draw strong conclusions on the effect of pregnancy on the pharmacokinetic parameters ofthese components of ACT. Novel approaches such as sampling methods using lower bloodvolumes and minimal preparation (e.g. dried blood spots, high sensitive drug assays), andpopulation pharmacokinetics analysis that are able to investigate the effect of variables suchas age, pregnancy, simultaneously administered drugs, can generate solid data that caninform treatment of malaria in pregnancy.461

Electronic supplementary material

Additional file 1. Methods section. This additional file describes the full methods and searchstrategy.

Additional file 2. Ongoing trials. This additional file summarized ongoing clinical trials onthe subject.

Additional file 3. Quality of included studies. This additional file shows the results of thequality assessment of the individual included studies.

Additional file 4. Data sheet. This additional file shows the original data as extracted fromthe included studies.

Tab

le 1

.Ove

rvie

w a

nd su

mm

ary

of in

clud

ed st

udie

s

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Ben

jam

in(2

015)

Papu

a N

ewG

uine

e (n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

4wks

)an

d ag

e-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

with

mal

aria

infe

ctio

n.

Gro

up 1

DH

A-P

PQ(7

/58

mg/

kgp.

o. q

.d. f

or3

days

)

Gro

up 2

PPQ

(128

0mg

p.o.

q.d

. for

3 da

ys) +

SP

(25m

g/kg

once

)

32 p

regn

ant

wom

en33

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

MTT

, NN

,C

L/F,

Vc/

F,Q

/F, V

p/F,

t 1/2,

AU

C0-

∞.

Klo

prog

ge(2

015)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)w

ithou

t mal

aria

.

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te(4

mg/

kg)

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen Gro

up 2

: 10

wom

en14

pos

tpar

tum

Com

partm

ent

al a

naly

sis

AU

C0-

12,

Cm

ax, T

max

,t 1/

2, C

L/F,

Vd/

F.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

McG

read

y(2

012)

.



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

p.o

q.d.

on

day

1-6

Gro

up 2

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

wom

en

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

edno

n-pr

egna

nt w

omen

with

P.

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

falc

ipar

umin

fect

ion.

AU

C0-

∞,

AU

C-

∞/d

ose.

Klo

prog

ge(2

013)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

115

preg

nant

wom

en26

ven

ous

sam

ples

89 c

apill

ary

sam

ples

17 n

on-

preg

nant

wom

en(a

ll ve

nous

sam

ples

)

Com

partm

ent

al a

naly

sis

AU

C0-

∞,

Cm

ax, T

1/2,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

Pio

la(2

010)

.

Tarn

ing

(201

3)U

gand

a(O

ct20

06–

May

2009

)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n w

ith a

nEG

A>1

3wks

& n

on-

preg

nant

wom

en m

atch

ed fo

rhi

stor

y of

feve

r, te

mp.

>

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

OR

AL:

21 p

regn

ant

wom

en

Lum

efan

trine

:26

pre

gnan

t

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

Res

ults

for

arte

met

her

and

dihy

droa

rtem

isi

nin

are

repo

rted

by



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

p.o

q.d.

on

day

1-6

Gro

up 2

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

wom

en

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

edno

n-pr

egna

nt w

omen

with

P.

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

falc

ipar

umin

fect

ion.

AU

C0-

∞,

AU

C-

∞/d

ose.

Klo

prog

ge(2

013)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

115

preg

nant

wom

en26

ven

ous

sam

ples

89 c

apill

ary

sam

ples

17 n

on-

preg

nant

wom

en(a

ll ve

nous

sam

ples

)

Com

partm

ent

al a

naly

sis

AU

C0-

∞,

Cm

ax, T

1/2,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

Pio

la(2

010)

.

Tarn

ing

(201

3)U

gand

a(O

ct20

06–

May

2009

)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n w

ith a

nEG

A>1

3wks

& n

on-

preg

nant

wom

en m

atch

ed fo

rhi

stor

y of

feve

r, te

mp.

>

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

OR

AL:

21 p

regn

ant

wom

en

Lum

efan

trine

:26

pre

gnan

t

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

Res

ults

for

arte

met

her

and

dihy

droa

rtem

isi

nin

are

repo

rted

by



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

37.5

°C, s

mok

ing

stat

us a

ndle

vel o

f par

asita

emia

.Q

uini

ne (1

0m

g/kg

p.o

.t.i

.d. f

or 7

days

)

wom

en17

non

-pr

egna

ntw

omen

Qui

nine

:21

pre

gnan

tw

omen

AU

C0-

∞,

AU

C-

∞/d

ose,

AU

C72

-last

,A

UC

72-∞

,da

y 7

conc

entra

tion.

Tarn

ing

(201

2-2)

.N

este

d in

larg

eref

ficac

y /

safe

ty st

udy

by P

iola

(201

0).

Ada

m(2

012)

Suda

n(A

ug20

07-F

eb20

08)

Clin

ical

trail

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

(afte

rdo

se 1

, 2an

d 3)

, Tm

ax

(afte

r dos

e1,

2 a

nd 3

),C

L/F,

V/F

,T 1

/2, A

UC

0-la

st, A

UC

0-∞

, AU

C-

∞/d

ose,

AU

C0-

24,

AU

C24

-48,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Hog

lund

(201

2).

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

AU

C48

-72,

AU

C72

-∞,

day

7 an

d 14

conc

entra

tion.

Hog

lund

(201

2)Su

dan

(Aug

2007

-Feb

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

48-9

0,A

UC

0-90

,da

y 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Ada

m (2

012)

.

McG

read

y(2

012)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen Gro

up 2

: 10

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-∞

,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Klo

prog

ge(2

015)

.



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

37.5

°C, s

mok

ing

stat

us a

ndle

vel o

f par

asita

emia

.Q

uini

ne (1

0m

g/kg

p.o

.t.i

.d. f

or 7

days

)

wom

en17

non

-pr

egna

ntw

omen

Qui

nine

:21

pre

gnan

tw

omen

AU

C0-

∞,

AU

C-

∞/d

ose,

AU

C72

-last

,A

UC

72-∞

,da

y 7

conc

entra

tion.

Tarn

ing

(201

2-2)

.N

este

d in

larg

eref

ficac

y /

safe

ty st

udy

by P

iola

(201

0).

Ada

m(2

012)

Suda

n(A

ug20

07-F

eb20

08)

Clin

ical

trail

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

(afte

rdo

se 1

, 2an

d 3)

, Tm

ax

(afte

r dos

e1,

2 a

nd 3

),C

L/F,

V/F

,T 1

/2, A

UC

0-la

st, A

UC

0-∞

, AU

C-

∞/d

ose,

AU

C0-

24,

AU

C24

-48,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Hog

lund

(201

2).

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

AU

C48

-72,

AU

C72

-∞,

day

7 an

d 14

conc

entra

tion.

Hog

lund

(201

2)Su

dan

(Aug

2007

-Feb

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

48-9

0,A

UC

0-90

,da

y 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Ada

m (2

012)

.

McG

read

y(2

012)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen Gro

up 2

: 10

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-∞

,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Klo

prog

ge(2

015)

.



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

preg

nant

wom

en w

ithP.

falc

ipar

umm

alar

ia.

and

28co

ncen

tratio

n.Ta

rnin

g(2

012-

2)U

gand

a(M

arch

2008

–Se

pt20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

60-

last

,A

UC

/dos

e.

Nes

ted

inla

rger

effic

acy

stud

yby

Pio

la(2

010)

.

Tarn

ing

(201

2-3)

Thai

land

(Oct

200

7-M

ay 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t(n

=12)

P. v

ivax

mal

aria

.

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

27 p

regn

ant

wom

en19

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

-la

st.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

1).

Mor

ris(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

T 1/2, C

L/F,

V/F

.B

ased

on

the

sam

e cl

inic

alst

udy

asO

nyam

boko

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

with

out m

alar

ia.

(4m

g/kg

)p.

o q.

d. o

nda

y 1-

6

Gro

up 2

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

14 p

ostp

artu

mw

omen

AU

C0-

∞/d

ose.

Tarn

ing

(201

2-1)

Thai

land

(Jun

e 20

08-

Dec

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

0-24

, AU

C0-

92, d

ay 7

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

2).



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

preg

nant

wom

en w

ithP.

falc

ipar

umm

alar

ia.

and

28co

ncen

tratio

n.Ta

rnin

g(2

012-

2)U

gand

a(M

arch

2008

–Se

pt20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

60-

last

,A

UC

/dos

e.

Nes

ted

inla

rger

effic

acy

stud

yby

Pio

la(2

010)

.

Tarn

ing

(201

2-3)

Thai

land

(Oct

200

7-M

ay 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t(n

=12)

P. v

ivax

mal

aria

.

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

27 p

regn

ant

wom

en19

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

-la

st.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

1).

Mor

ris(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

T 1/2, C

L/F,

V/F

.B

ased

on

the

sam

e cl

inic

alst

udy

asO

nyam

boko

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

with

out m

alar

ia.

(4m

g/kg

)p.

o q.

d. o

nda

y 1-

6

Gro

up 2

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

14 p

ostp

artu

mw

omen

AU

C0-

∞/d

ose.

Tarn

ing

(201

2-1)

Thai

land

(Jun

e 20

08-

Dec

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

0-24

, AU

C0-

92, d

ay 7

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

2).



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

para

sita

emia

& n

on-p

regn

ant

fem

ale

volu

ntee

rs w

ithas

ympt

omat

icP.

falc

ipar

umpa

rasi

taem

ia (2

00-3

00,0

00p/

µL).

Rijk

en(2

011-

1)Th

aila

nd(O

ct 2

007-

May

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t(n

=12)

P. v

ivax

mal

aria

.

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

24 p

regn

ant

wom

en18

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

AU

C0-

∞,

AU

C0-

∞/d

ose,

day

7 conc

entra

tion.

Bas

edon

the

sam

e cl

inic

alst

udy

asTa

rnin

g(2

012-

3)

Rijk

en(2

011-

2)Th

aila

nd(J

une

2008

-D

ec 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht<

25%

) with

unco

mpl

icat

edP.

falc

ipar

um

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

24 p

regn

ant

wom

en24

non

-pr

egna

nt

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,C

L/F,

V/F

,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

2012

-

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

tfe

mal

e vo

lunt

eers

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

).

(172

5 m

g)p.

o. q

.d. o

nda

y 1

25 n

on-

preg

nant

wom

en

(201

1).

Ony

ambo

ko(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

m

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F,V

/F,

t 1/2,

AU

C0-

∞.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Mor

ris(2

011)

.



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

para

sita

emia

& n

on-p

regn

ant

fem

ale

volu

ntee

rs w

ithas

ympt

omat

icP.

falc

ipar

umpa

rasi

taem

ia (2

00-3

00,0

00p/

µL).

Rijk

en(2

011-

1)Th

aila

nd(O

ct 2

007-

May

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t(n

=12)

P. v

ivax

mal

aria

.

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

24 p

regn

ant

wom

en18

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

AU

C0-

∞,

AU

C0-

∞/d

ose,

day

7 conc

entra

tion.

Bas

edon

the

sam

e cl

inic

alst

udy

asTa

rnin

g(2

012-

3)

Rijk

en(2

011-

2)Th

aila

nd(J

une

2008

-D

ec 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht<

25%

) with

unco

mpl

icat

edP.

falc

ipar

um

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

24 p

regn

ant

wom

en24

non

-pr

egna

nt

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,C

L/F,

V/F

,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

2012

-

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

tfe

mal

e vo

lunt

eers

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

).

(172

5 m

g)p.

o. q

.d. o

nda

y 1

25 n

on-

preg

nant

wom

en

(201

1).

Ony

ambo

ko(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

m

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F,V

/F,

t 1/2,

AU

C0-

∞.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Mor

ris(2

011)

.



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

mon

ths)

with

outP

.fa

lcip

arum

para

sita

emia

and

with

Hb>

8g/d

L(M

ozam

biqu

e &

Sud

an) &

mat

ched

non

-pre

gnan

tw

omen

with

acu

teun

com

plic

ated

falc

ipar

umm

alar

ia (M

ozam

biqu

e).

Piol

a (2

010)

Uga

nda

(Oct

2006

-May

2009

)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n (<

250,

000

p/µL

)w

ith a

n EG

A>1

3wks

and

Hb

> 7g

/dL.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

97 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lan

alys

is

Day

7co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

(201

2-2)

and

Tarn

ing

(201

3).

Kar

unaj

eew

a (2

009)

Papu

a N

ewG

uine

e(F

eb20

06-J

uly

2006

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithou

t sev

ere

mal

aria

(n=1

7:P.

falc

ipar

um/ v

ivax

/ m

alar

iae

para

sita

emia

; n=1

3: n

o

SP (1

500/

75m

g p.

o.on

ce) +

Chl

oroq

uine

(135

0 m

gp.

o. q

.d. f

or

30 p

regn

ant

wom

en30

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

mal

aria

& m

atch

ed n

on-

preg

nant

wom

en w

ithP.

f alc

ipar

umm

alar

ia.

days

)w

omen

t 1/2,

AU

C0-

last

, AU

C0-

∞, A

UC

0-∞

/dos

e,A

UC

0-24

,A

UC

24-4

8,A

UC

48-7

2,A

UC

72-∞

,da

y 7,

14

and

28co

ncen

tratio

n.

1.

Nyu

nt(2

010)

Mal

i,M

ozam

biqu

e, S

udan

&Za

mbi

a(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en w

ith a

nEG

A 1

5-36

wks

with

outP

.fa

lcip

arum

para

sita

emia

(Hb>

8g/d

L) &

sam

e w

omen

post

par

tum

(6-4

3wks

)w

ithou

tP. f

alci

paru

mpa

rasi

taem

ia a

nd w

ithH

b>8g

/dL

(Mal

i & Z

ambi

a)/ p

ostp

artu

m w

omen

(> 6

SP (1

500/

75m

g p.

o.on

ce)

97 p

regn

ant

wom

en77

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, CL/

F,V

/F, t

1/2,

AU

C0-

∞,

day

7co

ncen

tratio

n.



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

mon

ths)

with

outP

.fa

lcip

arum

para

sita

emia

and

with

Hb>

8g/d

L(M

ozam

biqu

e &

Sud

an) &

mat

ched

non

-pre

gnan

tw

omen

with

acu

teun

com

plic

ated

falc

ipar

umm

alar

ia (M

ozam

biqu

e).

Piol

a (2

010)

Uga

nda

(Oct

2006

-May

2009

)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n (<

250,

000

p/µL

)w

ith a

n EG

A>1

3wks

and

Hb

> 7g

/dL.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

97 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lan

alys

is

Day

7co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

(201

2-2)

and

Tarn

ing

(201

3).

Kar

unaj

eew

a (2

009)

Papu

a N

ewG

uine

e(F

eb20

06-J

uly

2006

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithou

t sev

ere

mal

aria

(n=1

7:P.

falc

ipar

um/ v

ivax

/ m

alar

iae

para

sita

emia

; n=1

3: n

o

SP (1

500/

75m

g p.

o.on

ce) +

Chl

oroq

uine

(135

0 m

gp.

o. q

.d. f

or

30 p

regn

ant

wom

en30

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

mal

aria

& m

atch

ed n

on-

preg

nant

wom

en w

ithP.

falc

ipar

umm

alar

ia.

days

)w

omen

t 1/2,

AU

C0-

last

, AU

C0-

∞, A

UC

0-∞

/dos

e,A

UC

0-24

,A

UC

24-4

8,A

UC

48-7

2,A

UC

72-∞

,da

y 7,

14

and

28co

ncen

tratio

n.

1.

Nyu

nt(2

010)

Mal

i,M

ozam

biqu

e, S

udan

&Za

mbi

a(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en w

ith a

nEG

A 1

5-36

wks

with

outP

.fa

lcip

arum

para

sita

emia

(Hb>

8g/d

L) &

sam

e w

omen

post

par

tum

(6-4

3wks

)w

ithou

tP. f

alci

paru

mpa

rasi

taem

ia a

nd w

ithH

b>8g

/dL

(Mal

i & Z

ambi

a)/ p

ostp

artu

m w

omen

(> 6

SP (1

500/

75m

g p.

o.on

ce)

97 p

regn

ant

wom

en77

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, CL/

F,V

/F, t

1/2,

AU

C0-

∞,

day

7co

ncen

tratio

n.



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

para

sita

emia

) & m

atch

edno

n-pr

egna

nt w

omen

(n=9

:fa

lcip

arum

/ vi

vax

/ mal

aria

epa

rasi

taem

ia; n

=21:

no

para

sita

emia

).

3 da

ys)

Tarn

ing

(200

9)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithun

com

plic

ated

sym

ptom

atic

P. fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

-25

0 m

lch

ocol

ate

milk

(6-7

gfa

t)

103

preg

nant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

CL/

F, V

/F,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

McG

read

y(2

008)

.

McG

read

y(2

008)

Thai

land

(Apr

il 20

04-

Aug

2006

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith a

cute

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

85 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lan

alys

is

Day

7co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

McG

read

y(2

006-

2) a

ndTa

rnin

g(2

009)

.

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Gre

en(2

007)

Ken

ya(1

999-

2000

)C

linic

altri

alPr

imi-

and

secu

ndig

ravi

dw

omen

with

unc

ompl

icat

edsi

ngle

ton

preg

nanc

ies w

ithEG

A 1

6-28

wks

and

Hb>

8g/d

Lw

ithou

tsy

mpt

omat

ic m

alar

ia (n

=11:

para

sita

emic

; n=2

2:ap

aras

itaem

ic) &

sam

ew

omen

pos

t par

tum

(2-3

mon

ths)

with

out

sym

ptom

atic

mal

aria

(n=1

:pa

rasi

taem

ic; n

=10:

apar

asita

emic

).

SP (1

500/

75m

g p.

o.on

ce)

33 p

regn

ant

wom

en16

HIV

-po

sitiv

e17

HIV

-ne

gativ

e11

pos

tpar

tum

wom

en6

HIV

-po

sitiv

e5

HIV

-ne

gativ

e

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

McG

read

y(2

006-

1)Th

aila

nd(O

ct 2

000-

July

200

1)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 2

00m

Lch

ocol

ate

milk

(8%

24N

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C48

-72

.



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

para

sita

emia

) & m

atch

edno

n-pr

egna

nt w

omen

(n=9

:fa

lcip

arum

/ vi

vax

/ mal

aria

epa

rasi

taem

ia; n

=21:

no

para

sita

emia

).

3 da

ys)

Tarn

ing

(200

9)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithun

com

plic

ated

sym

ptom

atic

P. fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

-25

0 m

lch

ocol

ate

milk

(6-7

gfa

t)

103

preg

nant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

CL/

F, V

/F,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

McG

read

y(2

008)

.

McG

read

y(2

008)

Thai

land

(Apr

il 20

04-

Aug

2006

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith a

cute

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

85 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lan

alys

is

Day

7co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

McG

read

y(2

006-

2) a

ndTa

rnin

g(2

009)

.

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Gre

en(2

007)

Ken

ya(1

999-

2000

)C

linic

altri

alPr

imi-

and

secu

ndig

ravi

dw

omen

with

unc

ompl

icat

edsi

ngle

ton

preg

nanc

ies w

ithEG

A 1

6-28

wks

and

Hb>

8g/d

Lw

ithou

tsy

mpt

omat

ic m

alar

ia (n

=11:

para

sita

emic

; n=2

2:ap

aras

itaem

ic) &

sam

ew

omen

pos

t par

tum

(2-3

mon

ths)

with

out

sym

ptom

atic

mal

aria

(n=1

:pa

rasi

taem

ic; n

=10:

apar

asita

emic

).

SP (1

500/

75m

g p.

o.on

ce)

33 p

regn

ant

wom

en16

HIV

-po

sitiv

e17

HIV

-ne

gativ

e11

pos

tpar

tum

wom

en6

HIV

-po

sitiv

e5

HIV

-ne

gativ

e

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

McG

read

y(2

006-

1)Th

aila

nd(O

ct 2

000-

July

200

1)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 2

00m

Lch

ocol

ate

milk

(8%

24N

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C48

-72

.



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

fat)

McG

read

y(2

006-

2)Th

aila

nd(A

pril

2004

-Au

g 20

04)

Clin

ical

trial

Preg

nant

wom

en in

the

seco

nd a

nd th

ird tr

imes

ter o

fpr

egna

ncy

with

recr

udes

cent

unco

mpl

icat

ed m

ulti-

drug

resi

stan

tP. f

alci

paru

mm

alar

ia a

fter 7

-day

qui

nine

treat

men

t.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

13 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

24, A

UC

60-8

4,A

UC

/dos

e.

Na

Ban

gcha

ng(2

005)

Thai

land

(Nov

200

0-A

pril

2001

)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

with

acut

e sy

mpt

omat

icP.

falc

ipar

umm

onoi

nfec

tion

and

Hb>

8g/d

L.

AP

(100

0/40

0m

g p.

o. q

.d.

for 3

day

s)

26 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sC

max

, Tm

ax,

AU

C0-

∞,

PG-C

Gra

tio.

McG

read

y(2

003-

1)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntm

ulti-

drug

resi

stan

tun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 3

00m

Lch

ocol

ate

24 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,A

UC

0-∞

,A

UC

48-∞

.

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

milk

(8%

fat)

McG

read

y(2

003-

2)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Hea

lthy

preg

nant

wom

enw

ith a

n EG

A>3

5wks

& sa

me

wom

en p

ost p

artu

m (>

2m

onth

s).

Prog

uani

l(2

00 m

g p.

o.on

ce)

45 p

regn

ant

wom

en45

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

(pla

sma

and

urin

e),

6h conc

entra

tion

(pla

sma

and

urin

e).

Na

Ban

gcha

ng(1

994)

Thai

land

(Sep

t 198

6-Ju

ne 1

988)

Clin

ical

trial

Preg

nant

wom

en in

firs

t(n

=2) a

nd th

ird (n

=7)

trim

este

r of p

regn

ancy

with

P. fa

lcip

arum

para

sita

emia

& n

on-p

regn

ant w

omen

mat

ched

for a

ge w

ithP.

falc

ipar

umpa

rasi

taem

ia.

Mef

loqu

ine

(15

mg/

kg)

9 pr

egna

ntw

omen

8 no

n-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2.

Wan

gboo

nsku

l (19

93)

Thai

land

(not

repo

rted

)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

with

outP

. fal

cipa

rum

mal

aria

& sa

me

wom

en p

ost

partu

m (>

2 m

onth

s) w

ithou

t

Prog

uani

l(2

00 m

g p.

o.on

ce)

10 p

regn

ant

wom

en4

post

partu

mw

omen

9 m

ale

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

t 1/2,

AU

C.



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

fat)

McG

read

y(2

006-

2)Th

aila

nd(A

pril

2004

-Au

g 20

04)

Clin

ical

trial

Preg

nant

wom

en in

the

seco

nd a

nd th

ird tr

imes

ter o

fpr

egna

ncy

with

recr

udes

cent

unco

mpl

icat

ed m

ulti-

drug

resi

stan

tP. f

alci

paru

mm

alar

ia a

fter 7

-day

qui

nine

treat

men

t.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

13 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

24, A

UC

60-8

4,A

UC

/dos

e.

Na

Ban

gcha

ng(2

005)

Thai

land

(Nov

200

0-A

pril

2001

)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

with

acut

e sy

mpt

omat

icP.

falc

ipar

umm

onoi

nfec

tion

and

Hb>

8g/d

L.

AP

(100

0/40

0m

g p.

o. q

.d.

for 3

day

s)

26 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sC

max

, Tm

ax,

AU

C0-

∞,

PG-C

Gra

tio.

McG

read

y(2

003-

1)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntm

ulti-

drug

resi

stan

tun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 3

00m

Lch

ocol

ate

24 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,A

UC

0-∞

,A

UC

48-∞

.

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

milk

(8%

fat)

McG

read

y(2

003-

2)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Hea

lthy

preg

nant

wom

enw

ith a

n EG

A>3

5wks

& sa

me

wom

en p

ost p

artu

m (>

2m

onth

s).

Prog

uani

l(2

00 m

g p.

o.on

ce)

45 p

regn

ant

wom

en45

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

(pla

sma

and

urin

e),

6h conc

entra

tion

(pla

sma

and

urin

e).

Na

Ban

gcha

ng(1

994)

Thai

land

(Sep

t 198

6-Ju

ne 1

988)

Clin

ical

trial

Preg

nant

wom

en in

firs

t(n

=2) a

nd th

ird (n

=7)

trim

este

r of p

regn

ancy

with

P. fa

lcip

arum

para

sita

emia

& n

on-p

regn

ant w

omen

mat

ched

for a

ge w

ithP.

falc

ipar

umpa

rasi

taem

ia.

Mef

loqu

ine

(15

mg/

kg)

9 pr

egna

ntw

omen

8 no

n-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2.

Wan

gboo

nsku

l (19

93)

Thai

land

(not

repo

rted

)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

with

outP

. fal

cipa

rum

mal

aria

& sa

me

wom

en p

ost

partu

m (>

2 m

onth

s) w

ithou

t

Prog

uani

l(2

00 m

g p.

o.on

ce)

10 p

regn

ant

wom

en4

post

partu

mw

omen

9 m

ale

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

t 1/2,

AU

C.



Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

P. fa

lcip

arum

mal

aria

&he

alth

y ad

ult m

ale

volu

ntee

rsw

ithou

tP. f

alci

paru

mm

alar

ia*.

patie

nts*

Nos

ten

(199

0)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

.G

roup

1:

Mef

loqu

ine

(250

mg

per

wee

k)

Gro

up 2

:M

eflo

quin

e(1

25 m

g pe

rw

eek)

20 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sC

max

, Tm

ax,

CL/

F, t 1

/2,

AU

C.

q.d.

= o

nce

a da

y; b

.i.d.

= tw

ice

ada

y; t.

i.d. =

thre

e tim

es a

day

; p.o

. = p

er o

s (or

al);

i.v. (

intra

veno

us);

AL

= ar

tem

ethe

r-lu

mef

antri

ne; D

HA

-PPQ

=di

hydr

oarte

mis

inin

-pip

eraq

uine

; SP

= Su

lfado

xine

-Pyr

imet

ham

ine;

AP

= at

ovaq

uone

-pro

guan

il; P

G =

pro

guan

il; C

G =

cyc

logu

anil;

Cm

ax=

max

imum

c onc

entra

tion

afte

r adm

inis

tratio

n; T

max

= tim

e to

max

imum

con

cent

ratio

n af

ter a

dmin

istra

tion;

CL/

F =

oral

cle

aran

ce; V

/F =

app

aren

t vol

ume

ofdi

strib

utio

n; t 1

/2=

half-

life;

AU

C =

are

a un

der t

he c

urve

(exp

osur

e); H

b =

haem

oglo

bin;

Ht =

hae

mat

ocrit

; wks

= w

eeks

;*

Dat

a fo

r mal

e su

bjec

ts w

ere

incl

uded

from

a pr

evio

us st

udy

for c

ompa

rison

.

Tab

le 2

.Prim

ary

stud

y ou

tcom

es p

er c

ompo

und

Art

emet

her

Aut

hor

(yea

r)C

ount

ry (t

ime

peri

od)

Popu

latio

nD

rug

(dos

e)N

umbe

r of

wom

enR

esul

t

Tarn

ing

(201

3)U

gand

a(O

ct20

06–

May

2009

)

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n w

ith a

n EG

A>1

3wks

& n

on-p

regn

ant w

omen

mat

ched

for h

isto

ry o

f fev

er,

tem

p. >

37.

5°C

, sm

okin

g st

atus

and

leve

l of p

aras

itaem

ia.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enEs

timat

ed e

xpos

ure

to a

rtem

ethe

r and

DH

A w

as si

mila

r to

that

pre

viou

sly

repo

rted

in p

regn

ant T

hai p

atie

nts a

ndlo

wer

than

repo

rted

in a

dult

non-

preg

nant

Tha

i pat

ient

s.

Tarn

ing

(201

2-2)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Preg

nant

wom

en in

seco

nd a

ndth

ird tr

imes

ter o

f pre

gnan

cy(E

GA

>13w

ks) w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enN

o st

atis

tical

ly si

gnifi

cant

diff

eren

ces i

n ph

arm

acok

inet

icpr

oper

ties b

etw

een

seco

nd a

nd th

ird tr

imes

ter.

McG

read

y(2

006-

2)Th

aila

nd

(Apr

il20

04-

Preg

nant

wom

en in

the

seco

ndan

d th

ird tr

imes

ter o

f pre

gnan

cyw

ith re

crud

esce

nt

AL

(80/

480

mg

p.o.

13 p

regn

ant

wom

enN

o si

gnifi

cant

diff

eren

ces i

n th

e ph

arm

acok

inet

icpa

ram

eter

s of a

rtem

ethe

r and

DH

A b

etw

een

the

seco

ndan

d th

ird tr

imes

ter.

Com

paris

on w

ith d

ata

from

lite

ratu

re



5

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

P. fa

lcip

arum

mal

aria

&he

alth

y ad

ult m

ale

volu

ntee

rsw

ithou

tP. f

alci

paru

mm

alar

ia*.

patie

nts*

Nos

ten

(199

0)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

.G

roup

1:

Mef

loqu

ine

(250

mg

per

wee

k)

Gro

up 2

:M

eflo

quin

e(1

25 m

g pe

rw

eek)

20 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sC

max

, Tm

ax,

CL/

F, t 1

/2,

AU

C.

q.d.

= o

nce

a da

y; b

.i.d.

= tw

ice

ada

y; t.

i.d. =

thre

e tim

es a

day

; p.o

. = p

er o

s (or

al);

i.v. (

intra

veno

us);

AL

= ar

tem

ethe

r-lu

mef

antri

ne; D

HA

-PPQ

=di

hydr

oarte

mis

inin

-pip

eraq

uine

; SP

= Su

lfado

xine

-Pyr

imet

ham

ine;

AP

= at

ovaq

uone

-pro

guan

il; P

G =

pro

guan

il; C

G =

cyc

logu

anil;

Cm

ax=

max

imum

conc

entra

tion

afte

r adm

inis

tratio

n; T

max

= tim

e to

max

imum

con

cent

ratio

n af

ter a

dmin

istra

tion;

CL/

F =

oral

cle

aran

ce; V

/F =

app

aren

t vol

ume

ofdi

strib

utio

n; t 1

/2=

half-

life;

AU

C =

are

a un

der t

he c

urve

(exp

osur

e); H

b =

haem

oglo

bin;

Ht =

hae

mat

ocrit

; wks

= w

eeks

;*

Dat

a fo

r mal

e su

bjec

ts w

ere

incl

uded

from

a pr

evio

us st

udy

for c

ompa

rison

.

Tab

le 2

.Prim

ary

stud

y ou

tcom

es p

er c

ompo

und

Art

emet

her

Aut

hor

(yea

r)C

ount

ry (t

ime

peri

od)

Popu

latio

nD

rug

(dos

e)N

umbe

r of

wom

enR

esul

t

Tarn

ing

(201

3)U

gand

a(O

ct20

06–

May

2009

)

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n w

ith a

n EG

A>1

3wks

& n

on-p

regn

ant w

omen

mat

ched

for h

isto

ry o

f fev

er,

tem

p. >

37.

5°C

, sm

okin

g st

atus

and

leve

l of p

aras

itaem

ia.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enEs

timat

ed e

xpos

ure

to a

rtem

ethe

r and

DH

A w

as si

mila

r to

that

pre

viou

sly

repo

rted

in p

regn

ant T

hai p

atie

nts a

ndlo

wer

than

repo

rted

in a

dult

non-

preg

nant

Tha

i pat

ient

s.

Tarn

ing

(201

2-2)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Preg

nant

wom

en in

seco

nd a

ndth

ird tr

imes

ter o

f pre

gnan

cy(E

GA

>13w

ks) w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enN

o st

atis

tical

ly si

gnifi

cant

diff

eren

ces i

n ph

arm

acok

inet

icpr

oper

ties b

etw

een

seco

nd a

nd th

ird tr

imes

ter.

McG

read

y(2

006-

2)Th

aila

nd

(Apr

il20

04-

Preg

nant

wom

en in

the

seco

ndan

d th

ird tr

imes

ter o

f pre

gnan

cyw

ith re

crud

esce

nt

AL

(80/

480

mg

p.o.

13 p

regn

ant

wom

enN

o si

gnifi

cant

diff

eren

ces i

n th

e ph

arm

acok

inet

icpa

ram

eter

s of a

rtem

ethe

r and

DH

A b

etw

een

the

seco

ndan

d th

ird tr

imes

ter.

Com

paris

on w

ith d

ata

from

lite

ratu

re



Aug

2004

)un

com

plic

ated

mul

ti-dr

ugre

sist

antP

. fal

cipa

rum

mal

aria

afte

r 7-d

ay q

uini

ne tr

eatm

ent.

b.i.d

. for

3da

ys) +

250

ml

choc

olat

em

ilk (7

gfa

t)

show

ed a

low

er A

UC

and

Cm

ax o

f arte

met

her c

ompa

red

to m

ale

Thai

pat

ient

s and

of D

HA

com

pare

d to

non

-pr

egna

nt p

atie

nts.

Art

esun

ate

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Klo

prog

ge(2

015)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)w

ithou

t mal

aria

.

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te(4

mg/

kg)

p.o

q.d.

on

day

1-6

Gro

up 2

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen

Gro

up 2

: 10

wom

en14

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

AU

C0-

12,

Cm

ax, T

max

,t 1/

2, C

L/F,

Vd/

F.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

McG

read

y(2

012)

.

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

edno

n-pr

egna

nt w

omen

with

P.fa

lcip

arum

infe

ctio

n.

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

AU

C0-

∞,

AU

C-

∞/d

ose.

McG

read

y(2

012)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen

Gro

up 2

: 10

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-∞

,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Klo

prog

ge(2

015)

.



5

Aug

2004

)un

com

plic

ated

mul

ti-dr

ugre

sist

antP

. fal

cipa

rum

mal

aria

afte

r 7-d

ay q

uini

ne tr

eatm

ent.

b.i.d

. for

3da

ys) +

250

ml

choc

olat

em

ilk (7

gfa

t)

show

ed a

low

er A

UC

and

Cm

ax o

f arte

met

her c

ompa

red

to m

ale

Thai

pat

ient

s and

of D

HA

com

pare

d to

non

-pr

egna

nt p

atie

nts.

Art

esun

ate

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Klo

prog

ge(2

015)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)w

ithou

t mal

aria

.

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te(4

mg/

kg)

p.o

q.d.

on

day

1-6

Gro

up 2

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen

Gro

up 2

: 10

wom

en14

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

AU

C0-

12,

Cm

ax, T

max

,t 1/

2, C

L/F,

Vd/

F.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

McG

read

y(2

012)

.

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

edno

n-pr

egna

nt w

omen

with

P.fa

lcip

arum

infe

ctio

n.

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

AU

C0-

∞,

AU

C-

∞/d

ose.

McG

read

y(2

012)

Thai

land

(Apr

il 20

08–

Mar

ch20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen

Gro

up 2

: 10

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-∞

,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Klo

prog

ge(2

015)

.



with

out m

alar

ia.

(4m

g/kg

)p.

o q.

d. o

nda

y 1-

6G

roup

2A

rtesu

nate

(4 m

g/kg

)p.

o. q

.d. o

nda

y 0;

arte

suna

te (4

mg/

kg) i

.v.

q.d.

on

day

1, a

rtesu

nate

(4 m

g/kg

)p.

o.q.

d. o

nda

y 2-

6)

14 p

ostp

artu

mw

omen

AU

C0-

∞/d

ose.

Mor

ris(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

t

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

T 1/2, C

L/F,

V/F

.B

ased

on

the

sam

e cl

inic

alst

udy

asO

nyam

boko

(201

1).

fem

ale

volu

ntee

rs w

ithas

ympt

omat

icP.

falc

ipar

umpa

rasi

taem

ia (2

00-3

00,0

00p/

µL).

Ony

ambo

ko(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

enin

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

tfe

mal

e vo

lunt

eers

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

).

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Mor

ris(2

011)

.

McG

read

y(2

006-

1)Th

aila

nd(O

ct 2

000-

July

200

1)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 2

00m

Lch

ocol

ate

24N

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C48

-72

.



5

with

out m

alar

ia.

(4m

g/kg

)p.

o q.

d. o

nda

y 1-

6G

roup

2A

rtesu

nate

(4 m

g/kg

)p.

o. q

.d. o

nda

y 0;

arte

suna

te (4

mg/

kg) i

.v.

q.d.

on

day

1, a

rtesu

nate

(4 m

g/kg

)p.

o.q.

d. o

nda

y 2-

6)

14 p

ostp

artu

mw

omen

AU

C0-

∞/d

ose.

Mor

ris(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

t

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

T 1/2, C

L/F,

V/F

.B

ased

on

the

sam

e cl

inic

alst

udy

asO

nyam

boko

(201

1).

fem

ale

volu

ntee

rs w

ithas

ympt

omat

icP.

falc

ipar

umpa

rasi

taem

ia (2

00-3

00,0

00p/

µL).

Ony

ambo

ko(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

enin

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

tfe

mal

e vo

lunt

eers

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

).

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Mor

ris(2

011)

.

McG

read

y(2

006-

1)Th

aila

nd(O

ct 2

000-

July

200

1)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 2

00m

Lch

ocol

ate

24N

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C48

-72

.



milk

(8%

fat)

Dih

ydro

arte

mis

inin

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Ben

jam

in(2

015)

Papu

a N

ewG

uine

e (…

)C

linic

altri

alPr

egna

nt w

omen

in se

cond

and

third

trim

este

r of

preg

nanc

y(E

GA

>14w

ks)

and

age-

mat

ched

non

-pr

egna

nt w

omen

with

unco

mpl

icat

ed w

ith m

alar

iain

fect

ion.

Gro

up 1

DH

A-P

PQ(7

/58

mg/

kgp.

o. q

.d. f

or3

days

)

Gro

up 2

PPQ

(128

0mg

p.o.

q.d

. for

3 da

ys) +

SP

(25m

g/kg

once

)

32 p

regn

ant

wom

en33

non

-pr

egna

ntw

omen

Com

partm

ent

alan

alys

isM

TT, N

N,

CL/

F, V

c/F,

Q/F

, Vp/

F,t 1/

2, A

UC

0-∞

.

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

ed

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,

non-

preg

nant

wom

en w

ithP.

falc

ipar

umin

fect

ion.

AU

C0-

last

,A

UC

0-∞

,A

UC

-∞

/dos

e.M

cGre

ady

(201

2)Th

aila

nd(A

pril

2008

–M

arch

2009

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)w

ithou

t mal

aria

.

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te(4

mg/

kg)

p.o

q.d.

on

day

1-6

Gro

up 2

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen Gro

up 2

: 10

wom

en14

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-∞

,A

UC

0-∞

/dos

e.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Klo

prog

ge(2

015)

.



5

milk

(8%

fat)

Dih

ydro

arte

mis

inin

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Ben

jam

in(2

015)

Papu

a N

ewG

uine

e (…

)C

linic

altri

alPr

egna

nt w

omen

in se

cond

and

third

trim

este

r of

preg

nanc

y(E

GA

>14w

ks)

and

age-

mat

ched

non

-pr

egna

nt w

omen

with

unco

mpl

icat

ed w

ith m

alar

iain

fect

ion.

Gro

up 1

DH

A-P

PQ(7

/58

mg/

kgp.

o. q

.d. f

or3

days

)

Gro

up 2

PPQ

(128

0mg

p.o.

q.d

. for

3 da

ys) +

SP

(25m

g/kg

once

)

32 p

regn

ant

wom

en33

non

-pr

egna

ntw

omen

Com

partm

ent

alan

alys

isM

TT, N

N,

CL/

F, V

c/F,

Q/F

, Vp/

F,t 1/

2, A

UC

0-∞

.

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

ed

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,

non-

preg

nant

wom

en w

ithP.

falc

ipar

umin

fect

ion.

AU

C0-

last

,A

UC

0-∞

,A

UC

-∞

/dos

e.M

cGre

ady

(201

2)Th

aila

nd(A

pril

2008

–M

arch

2009

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

the

sam

e w

omen

post

par

tum

(3 m

onth

s)w

ithou

t mal

aria

.

Gro

up 1

Arte

suna

te(4

mg/

kg)

i.v. q

.d. o

nda

y 0;

arte

suna

te(4

mg/

kg)

p.o

q.d.

on

day

1-6

Gro

up 2

Arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

0;ar

tesu

nate

(4m

g/kg

) i.v

.q.

d. o

n da

y1,

arte

suna

te(4

mg/

kg)

p.o.

q.d

. on

day

2-6)

20 p

regn

ant

wom

enG

roup

1: 1

0w

omen Gro

up 2

: 10

wom

en14

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,A

UC

0-∞

,A

UC

0-∞

/dos

e.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Klo

prog

ge(2

015)

.



Tarn

ing

(201

2-1)

Thai

land

(Jun

e 20

08-

Dec

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

0-24

, AU

C0-

92, d

ay 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

2).

Tarn

ing

(201

2-2)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

60-

last

,A

UC

/dos

e.

Nes

ted

inla

rger

effic

acy

stud

yby

Pio

la(2

010)

.

Mor

ris(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

t

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

T 1/2, C

L/F,

V/F

.B

ased

on

the

sam

e cl

inic

alst

udy

asO

nyam

boko

(201

1).

fem

ale

volu

ntee

rs w

ithas

ympt

omat

icP.

falc

ipar

umpa

rasi

taem

ia (2

00-3

00,0

00p/

µL).

Ony

ambo

ko(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

tfe

mal

e vo

lunt

eers

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

).

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o.q.

d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Mor

ris(2

011)

.

Rijk

en(2

011-

2)Th

aila

nd(J

une

2008

-D

ec 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht<

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,C

L/F,

V/F

,t 1/

2, A

UC

0-la

st, A

UC

0-∞

, AU

C0-

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

2012

-1.



5

Tarn

ing

(201

2-1)

Thai

land

(Jun

e 20

08-

Dec

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

0-24

, AU

C0-

92, d

ay 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

2).

Tarn

ing

(201

2-2)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

21 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

Cm

ax, T

max

,C

L/F,

V/F

,t 1/

2, A

UC

60-

last

,A

UC

/dos

e.

Nes

ted

inla

rger

effic

acy

stud

yby

Pio

la(2

010)

.

Mor

ris(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

t

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o. q

.d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

T 1/2, C

L/F,

V/F

.B

ased

on

the

sam

e cl

inic

alst

udy

asO

nyam

boko

(201

1).

fem

ale

volu

ntee

rs w

ithas

ympt

omat

icP.

falc

ipar

umpa

rasi

taem

ia (2

00-3

00,0

00p/

µL).

Ony

ambo

ko(2

011)

DR

C(M

ay20

07-N

ov20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

nd(2

2-26

wks

) and

third

(32-

36w

ks) t

rimes

ter o

fpr

egna

ncy

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

; Ht>

30%

) & sa

me

wom

en p

ost p

artu

m (3

mon

ths)

with

(n=2

) or

with

out (

n=24

)P. f

alci

paru

mpa

rasi

taem

ia &

non

-pre

gnan

tfe

mal

e vo

lunt

eers

with

asym

ptom

atic

P. fa

lcip

arum

para

sita

emia

(200

-300

,000

p/µL

).

Arte

suna

te(2

00 m

g)p.

o. q

.d. o

nda

y 0

+ SP

(172

5 m

g)p.

o.q.

d. o

nda

y 1

26 p

regn

ant

wom

en26

pos

tpar

tum

wom

en25

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Mor

ris(2

011)

.

Rijk

en(2

011-

2)Th

aila

nd(J

une

2008

-D

ec 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht<

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,C

L/F,

V/F

,t 1/

2, A

UC

0-la

st, A

UC

0-∞

, AU

C0-

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

2012

-1.



∞/d

ose,

AU

C0-

24,

AU

C24

-48,

AU

C48

-72,

AU

C72

-∞,

d ay

7, 1

4an

d 28

conc

entra

tion.

McG

read

y(2

006-

1)Th

aila

nd(O

ct 2

000-

July

200

1)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 2

00m

Lch

ocol

ate

milk

(8%

fat)

24N

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C48

-72

.

McG

read

y(2

006-

2)Th

aila

nd(A

pril

2004

-Au

g 20

04)

Clin

ical

trial

Preg

nant

wom

en in

the

seco

nd a

nd th

ird tr

imes

ter o

fpr

egna

ncy

with

recr

udes

cent

unco

mpl

icat

ed m

ulti-

drug

resi

stan

tP. f

alci

paru

mm

alar

ia a

fter 7

-day

qui

nine

treat

men

t.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

13 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

24, A

UC

60-8

4,A

UC

/dos

e.

Lum

efan

trin

eA

utho

r(y

ear)

Cou

ntry

(tim

epe

riod

)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Klo

prog

ge(2

013)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

115

preg

nant

wom

en26

ven

ous

sam

ples

89 c

apill

ary

sam

ples

17 n

on-

preg

nant

wom

en(a

ll ve

nous

sam

ples

)

Com

partm

ent

al a

naly

sis

AU

C0-

∞,

Cm

ax, T

1/2,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

Pio

la(2

010)

.

Tarn

ing

(201

3)U

gand

a(O

ct20

06–

May

2009

)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n w

ith a

nEG

A>1

3wks

& n

on-

preg

nant

wom

en m

atch

ed fo

r

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

AL:

21 p

regn

ant

wom

en

Lum

efan

trine

:

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,

Res

ults

for

arte

met

her

and

dihy

droa

rtem

isi

nin

are



5

∞/d

ose,

AU

C0-

24,

AU

C24

-48,

AU

C48

-72,

AU

C72

-∞,

day

7, 1

4an

d 28

conc

entra

tion.

McG

read

y(2

006-

1)Th

aila

nd(O

ct 2

000-

July

200

1)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ith re

crud

esce

ntun

com

plic

ated

P. fa

lcip

arum

mal

aria

afte

r 7-d

ay q

uini

netre

atm

ent a

nd H

t>25

%.

Arte

suna

te-

AP

(4/2

0/8

mg/

kg p

.o.

q.d.

for 3

days

) + 2

00m

Lch

ocol

ate

milk

(8%

fat)

24N

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C48

-72

.

McG

read

y(2

006-

2)Th

aila

nd(A

pril

2004

-Au

g 20

04)

Clin

ical

trial

Preg

nant

wom

en in

the

seco

nd a

nd th

ird tr

imes

ter o

fpr

egna

ncy

with

recr

udes

cent

unco

mpl

icat

ed m

ulti-

drug

resi

stan

tP. f

alci

paru

mm

alar

ia a

fter 7

-day

qui

nine

treat

men

t.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

13 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

24, A

UC

60-8

4,A

UC

/dos

e.

Lum

efan

trin

eA

utho

r(y

ear)

Cou

ntry

(tim

epe

riod

)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Klo

prog

ge(2

013)

Uga

nda

(Mar

ch20

08–

Sept

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

3wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

115

preg

nant

wom

en26

ven

ous

sam

ples

89 c

apill

ary

sam

ples

17 n

on-

preg

nant

wom

en(a

ll ve

nous

sam

ples

)

Com

partm

ent

al a

naly

sis

AU

C0-

∞,

Cm

ax, T

1/2,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

Pio

la(2

010)

.

Tarn

ing

(201

3)U

gand

a(O

ct20

06–

May

2009

)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n w

ith a

nEG

A>1

3wks

& n

on-

preg

nant

wom

en m

atch

ed fo

r

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

tea

AL:

21 p

regn

ant

wom

en

Lum

efan

trine

:

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,

Res

ults

for

arte

met

her

and

dihy

droa

rtem

isi

nin

are



hist

ory

of fe

ver,

tem

p. >

37.5

°C, s

mok

ing

stat

us a

ndle

vel o

f par

asita

emia

.

OR

Qui

nine

(10

mg/

kg p

.o.

t.i.d

. for

7da

ys)

26 p

regn

ant

wom

en17

non

-pr

egna

ntw

omen

Qui

nine

:21

pre

gnan

tw

omen

AU

C0-

last

,A

UC

0-∞

,A

UC

-∞

/dos

e,A

UC

72-la

st,

AU

C72

-∞,

day

7co

ncen

tratio

n.

repo

rted

byTa

rnin

g(2

012-

2).

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

Pio

la(2

010)

.Pi

ola

(201

0)U

gand

a(O

ct20

06-M

ay20

09)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n (<

250,

000

p/µL

)w

ith a

n EG

A>1

3wks

and

Hb

> 7g

/dL.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

97 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lan

alys

is

Day

7co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

(201

2-2)

and

Tarn

ing

(201

3).

Tarn

ing

(200

9)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithun

com

plic

ated

sym

ptom

atic

P. fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

-25

0 m

lch

ocol

ate

milk

(6-7

gfa

t)

103

preg

nant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

CL/

F, V

/F,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

McG

read

y(2

008)

.

McG

read

y(2

008)

Thai

land

(Apr

il 20

04-

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

AL

(80/

480

mg

p.o.

85 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lD

ay 7

conc

entra

tioB

ased

on

the

sam

e cl

inic

al

Aug

2006

)pr

egna

ncy

with

acu

teun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

anal

ysis

n.st

udy

asM

cGre

ady

(200

6-2)

and

Tarn

ing

(200

9).

McG

read

y(2

006-

2)Th

aila

nd(A

pril

2004

-Au

g 20

04)

Clin

ical

trial

Preg

nant

wom

en in

the

seco

nd a

nd th

ird tr

imes

ter o

fpr

egna

ncy

with

recr

udes

cent

unco

mpl

icat

ed m

ulti-

drug

resi

stan

tP. f

alci

paru

mm

alar

ia a

fter 7

-day

qui

nine

treat

men

t.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

13 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

24, A

UC

60-8

4,A

UC

/dos

e.

Am

odia

quin

eA

utho

r(y

ear)

Cou

ntry

(tim

epe

riod

)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Tarn

ing

(201

2-3)

Thai

land

(Oct

200

7-M

ay20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

27 p

regn

ant

wom

en19

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

-la

st.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

1).



5

hist

ory

of fe

ver,

tem

p. >

37.5

°C, s

mok

ing

stat

us a

ndle

vel o

f par

asita

emia

.

OR

Qui

nine

(10

mg/

kg p

.o.

t.i.d

. for

7da

ys)

26 p

regn

ant

wom

en17

non

-pr

egna

ntw

omen

Qui

nine

:21

pre

gnan

tw

omen

AU

C0-

last

,A

UC

0-∞

,A

UC

-∞

/dos

e,A

UC

72-la

st,

AU

C72

-∞,

day

7co

ncen

tratio

n.

repo

rted

byTa

rnin

g(2

012-

2).

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

Pio

la(2

010)

.Pi

ola

(201

0)U

gand

a(O

ct20

06-M

ay20

09)

Clin

ical

trial

Preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

infe

ctio

n (<

250,

000

p/µL

)w

ith a

n EG

A>1

3wks

and

Hb

> 7g

/dL.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

mL

milk

97 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lan

alys

is

Day

7co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

(201

2-2)

and

Tarn

ing

(201

3).

Tarn

ing

(200

9)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithun

com

plic

ated

sym

ptom

atic

P. fa

lcip

arum

mal

aria

.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

200

-25

0 m

lch

ocol

ate

milk

(6-7

gfa

t)

103

preg

nant

wom

enC

ompa

rtme

ntal

ana

lysi

sTo

tal d

ose,

CL/

F, V

/F,

day

7co

ncen

tratio

n.

Nes

ted

inla

rger

effic

acy

/sa

fety

stud

yby

McG

read

y(2

008)

.

McG

read

y(2

008)

Thai

land

(Apr

il 20

04-

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

AL

(80/

480

mg

p.o.

85 p

regn

ant

wom

enN

onco

mpa

rtm

enta

lD

ay 7

conc

entra

tioB

ased

on

the

sam

e cl

inic

al

Aug

2006

)pr

egna

ncy

with

acu

teun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

anal

ysis

n.st

udy

asM

cGre

ady

(200

6-2)

and

Tarn

ing

(200

9).

McG

read

y(2

006-

2)Th

aila

nd(A

pril

2004

-Au

g 20

04)

Clin

ical

trial

Preg

nant

wom

en in

the

seco

nd a

nd th

ird tr

imes

ter o

fpr

egna

ncy

with

recr

udes

cent

unco

mpl

icat

ed m

ulti-

drug

resi

stan

tP. f

alci

paru

mm

alar

ia a

fter 7

-day

qui

nine

treat

men

t.

AL

(80/

480

mg

p.o.

b.i.d

. for

3da

ys) +

250

ml c

hoco

late

milk

(7g

fat)

13 p

regn

ant

wom

enN

onco

mpa

rtm

enta

l &co

mpa

rtmen

tal a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2,

AU

C0-

24, A

UC

60-8

4,A

UC

/dos

e.

Am

odia

quin

eA

utho

r(y

ear)

Cou

ntry

(tim

epe

riod

)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Tarn

ing

(201

2-3)

Thai

land

(Oct

200

7-M

ay20

08)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

27 p

regn

ant

wom

en19

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

-la

st.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

1).



(n=1

2)P.

viv

axm

alar

ia.

Rijk

en(2

011-

1)Th

aila

nd(O

ct 2

007-

May

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t(n

=12)

P. v

ivax

mal

aria

.

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

24 p

regn

ant

wom

en18

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax,C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

AU

C0-

∞,

AU

C0-

∞/d

ose,

day

7 conc

entra

tion.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

(201

2-3)

Mef

loqu

ine

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

ed

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,

non-

preg

nant

wom

en w

ithP.

falc

ipar

umin

fect

ion.

AU

C0-

last

,A

UC

0-∞

,A

UC

-∞

/dos

e.N

aB

angc

hang

(199

4)

Thai

land

(Sep

t 198

6-Ju

ne 1

988)

Clin

ical

trial

Preg

nant

wom

en in

firs

t(n

=2) a

nd th

ird (n

=7)

trim

este

r of p

regn

ancy

with

P. fa

lcip

arum

para

sita

emia

& n

on-p

regn

ant w

omen

mat

ched

for a

ge w

ithP.

falc

ipar

umpa

rasi

taem

ia.

Mef

loqu

ine

(15

mg/

kg)

9 pr

egna

ntw

omen

8 no

n-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2.

Nos

ten

(199

0)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

.G

roup

1:

Mef

loqu

ine

(250

mg

per

wee

k)

Gro

up 2

:M

eflo

quin

e(1

25 m

g pe

rw

eek)

20 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sC

max

, Tm

ax,

CL/

F, t 1

/2,

AU

C.

Sulfa

doxi

ne-p

yrim

etha

min

eA

utho

r(y

ear)

Cou

ntry

(tim

epe

riod

)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

Phar

mac

okin

etic

vari

able

s

Rem

arks



5

(n=1

2)P.

viv

axm

alar

ia.

Rijk

en(2

011-

1)Th

aila

nd(O

ct 2

007-

May

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ters

of

preg

nanc

y w

ith a

cute

P.vi

vax

mon

oinf

ectio

n &

sam

ew

omen

pos

t par

tum

(84-

173

days

) with

(n=7

) or w

ithou

t(n

=12)

P. v

ivax

mal

aria

.

Am

odia

quin

e (1

0 m

g/kg

p.o.

q.d

. for

3 da

ys)

24 p

regn

ant

wom

en18

pos

tpar

tum

wom

en

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax,C

L/F,

V/F

, t1/

2,A

UC

0-la

st,

AU

C0-

∞,

AU

C0-

∞/d

ose,

day

7 conc

entra

tion.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Tarn

ing

(201

2-3)

Mef

loqu

ine

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks

Val

ea(2

014)

Bur

kina

Faso

(Sep

t20

08-J

an20

09)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

with

unco

mpl

icat

edP.

falc

ipar

umm

onoi

nfec

tion

& m

atch

ed

Mef

loqu

ine

+ A

rtesu

nate

(8/3

.6m

g/kg

q.d

.fo

r 3 d

ays)

24 p

regn

ant

wom

en23

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,T m

ax, C

L/F,

V/F

, t1/

2,

non-

preg

nant

wom

en w

ithP.

falc

ipar

umin

fect

ion.

AU

C0-

last

,A

UC

0-∞

,A

UC

-∞

/dos

e.N

aB

angc

hang

(199

4)

Thai

land

(Sep

t 198

6-Ju

ne 1

988)

Clin

ical

trial

Preg

nant

wom

en in

firs

t(n

=2) a

nd th

ird (n

=7)

trim

este

r of p

regn

ancy

with

P. fa

lcip

arum

para

sita

emia

& n

on-p

regn

ant w

omen

mat

ched

for a

ge w

ithP.

falc

ipar

umpa

rasi

taem

ia.

Mef

loqu

ine

(15

mg/

kg)

9 pr

egna

ntw

omen

8 no

n-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, Tm

ax,

CL/

F, V

/F,

t 1/2.

Nos

ten

(199

0)Th

aila

nd(n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

third

trim

este

r of p

regn

ancy

.G

roup

1:

Mef

loqu

ine

(250

mg

per

wee

k)

Gro

up 2

:M

eflo

quin

e(1

25 m

g pe

rw

eek)

20 p

regn

ant

wom

enC

ompa

rtme

ntal

ana

lysi

sC

max

, Tm

ax,

CL/

F, t 1

/2,

AU

C.

Sulfa

doxi

ne-p

yrim

etha

min

eA

utho

r(y

ear)

Cou

ntry

(tim

epe

riod

)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

Phar

mac

okin

etic

vari

able

s

Rem

arks



met

hodo

log

yN

yunt

(201

0)M

ali,

Moz

ambi

que,

Sud

an &

Zam

bia

(not

repo

rted

)

Clin

ical

trial

Preg

nant

wom

en w

ith a

nEG

A 1

5-36

wks

with

outP

.fa

lcip

arum

para

sita

emia

(Hb>

8g/d

L) &

sam

e w

omen

post

par

tum

(6-4

3wks

)w

ithou

tP. f

alci

paru

mpa

rasi

taem

ia a

nd w

ithH

b>8g

/dL

(Mal

i & Z

ambi

a)/ p

ostp

artu

m w

omen

(> 6

mon

ths)

with

outP

.fa

lcip

arum

para

sitae

mia

and

with

Hb>

8g/d

L(M

ozam

biqu

e &

Sud

an) &

mat

ched

non

-pre

gnan

tw

omen

with

acu

teun

com

plic

ated

falc

ipar

umm

alar

ia (M

ozam

biqu

e).

SP (1

500/

75m

g p.

o.on

ce)

97 p

regn

ant

wom

en77

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, CL/

F,V

/F, t

1/2,

AU

C0-

∞,

day

7co

ncen

tratio

n.

Kar

unaj

eew

a (2

009)

Papu

a N

ewG

uine

e(F

eb20

06-J

uly

2006

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithou

t sev

ere

mal

aria

(n=1

7:P.

falc

ipar

um/ v

ivax

/m

alar

iae

para

sita

emia

; n=1

3: n

opa

rasi

taem

ia) &

mat

ched

SP (1

500/

75m

g p.

o.on

ce)+

Chl

oroq

uine

(135

0 m

gp.

o. q

.d. f

or3

days

)

30 p

regn

ant

wom

en30

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

non-

preg

nant

wom

en (n

=9:

falc

ipar

um /

viva

x /m

alar

iae

para

sita

emia

; n=2

1: n

opa

rasi

taem

ia).

Gre

en(2

007)

Ken

ya(1

999-

2000

)C

linic

altri

alPr

imi-

and

secu

ndig

ravi

dw

omen

with

unc

ompl

icat

edsi

ngle

ton

preg

nanc

ies w

ithEG

A 1

6-28

wks

and

Hb>

8g/d

L w

ithou

tsy

mpt

omat

ic m

alar

ia (n

=11:

para

sita

emic

; n=2

2:ap

aras

itaem

ic) &

sam

ew

omen

pos

t par

tum

(2-3

mon

ths)

with

out

sym

ptom

atic

mal

aria

(n=1

:pa

rasi

taem

ic; n

=10:

apar

asita

emic

).

SP (1

500/

75m

g p.

o.on

ce)

33 p

regn

ant

wom

en16

HIV

-po

sitiv

e17

HIV

-ne

gativ

e11

pos

tpar

tum

wom

en6

HIV

-po

sitiv

e5

HIV

-ne

gativ

e

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Pipe

raqu

ine

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks



5

met

hodo

log

yN

yunt

(201

0)M

ali,

Moz

ambi

que,

Sud

an &

Zam

bia

(not

repo

rted

)

Clin

ical

trial

Preg

nant

wom

en w

ith a

nEG

A 1

5-36

wks

with

outP

.fa

lcip

arum

para

sita

emia

(Hb>

8g/d

L) &

sam

e w

omen

post

par

tum

(6-4

3wks

)w

ithou

tP. f

alci

paru

mpa

rasi

taem

ia a

nd w

ithH

b>8g

/dL

(Mal

i & Z

ambi

a)/ p

ostp

artu

m w

omen

(> 6

mon

ths)

with

outP

.fa

lcip

arum

para

sitae

mia

and

with

Hb>

8g/d

L(M

ozam

biqu

e &

Sud

an) &

mat

ched

non

-pre

gnan

tw

omen

with

acu

teun

com

plic

ated

falc

ipar

umm

alar

ia (M

ozam

biqu

e).

SP (1

500/

75m

g p.

o.on

ce)

97 p

regn

ant

wom

en77

pos

tpar

tum

wom

en

Com

partm

ent

al a

naly

sis

Tota

l dos

e,C

max

, CL/

F,V

/F, t

1/2,

AU

C0-

∞,

day

7co

ncen

tratio

n.

Kar

unaj

eew

a (2

009)

Papu

a N

ewG

uine

e(F

eb20

06-J

uly

2006

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndor

third

trim

este

r of

preg

nanc

y w

ithou

t sev

ere

mal

aria

(n=1

7:P.

falc

ipar

um/ v

ivax

/m

alar

iae

para

sita

emia

; n=1

3: n

opa

rasi

taem

ia) &

mat

ched

SP (1

500/

75m

g p.

o.on

ce)+

Chl

oroq

uine

(135

0 m

gp.

o. q

.d. f

or3

days

)

30 p

regn

ant

wom

en30

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

non-

preg

nant

wom

en (n

=9:

falc

ipar

um /

viva

x /m

alar

iae

para

sita

emia

; n=2

1: n

opa

rasi

taem

ia).

Gre

en(2

007)

Ken

ya(1

999-

2000

)C

linic

altri

alPr

imi-

and

secu

ndig

ravi

dw

omen

with

unc

ompl

icat

edsi

ngle

ton

preg

nanc

ies w

ithEG

A 1

6-28

wks

and

Hb>

8g/d

L w

ithou

tsy

mpt

omat

ic m

alar

ia (n

=11:

para

sita

emic

; n=2

2:ap

aras

itaem

ic) &

sam

ew

omen

pos

t par

tum

(2-3

mo n

ths)

with

out

sym

ptom

atic

mal

aria

(n=1

:pa

rasi

taem

ic; n

=10:

apar

asita

emic

).

SP (1

500/

75m

g p.

o.on

ce)

33 p

regn

ant

wom

en16

HIV

-po

sitiv

e17

HIV

-ne

gativ

e11

pos

tpar

tum

wom

en6

HIV

-po

sitiv

e5

HIV

-ne

gativ

e

Com

partm

ent

al a

naly

sis

CL/

F, V

/F,

t 1/2,

AU

C0-

∞.

Pipe

raqu

ine

Aut

hor

(yea

r)C

ount

ry(t

ime

peri

od)

Typ

e of

stud

yPo

pula

tion

Dru

g (d

ose)

Num

ber

ofw

omen

Phar

mac

okin

etic

anal

ytic

met

hodo

log

y

Phar

mac

okin

etic

vari

able

s

Rem

arks



Ben

jam

in(2

015)

Papu

a N

ewG

uine

e (n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

4wks

)an

d ag

e-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

with

mal

aria

infe

ctio

n.

Gro

up 1

DH

A-P

PQ(7

/58

mg/

kgp.

o. q

.d. f

or3

days

)

Gro

up 2

PPQ

(128

0mg

p.o.

q.d

. for

3 da

ys) +

SP

(25m

g/kg

once

)

32 p

regn

ant

wom

en33

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

MTT

, NN

,C

L/F,

Vc/

F,Q

/F, V

p/F,

t 1/2,

AU

C0-

∞.

Ada

m(2

012)

Suda

n(A

ug20

07-F

eb20

08)

Clin

ical

trail

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

(afte

rdo

se 1

, 2an

d 3)

, Tm

ax

(afte

r dos

e1,

2 a

nd 3

),C

L/F,

V/F

,T 1

/2, A

UC

0-la

st, A

UC

0-∞

, AU

C-

∞/d

ose,

AU

C0-

24,

AU

C24

-48,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Hog

lund

(201

2).

AU

C48

-72,

AU

C72

-∞,

day

7 an

d 14

conc

entra

tion.

Hog

lund

(201

2)Su

dan

(Aug

2007

-Feb

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

48-9

0,A

UC

0-90

,da

y 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Ada

m (2

012)

.

Tarn

ing

(201

2-1)

Thai

land

(Jun

e 20

08-

Dec

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,t1

/2, A

UC

0-24

, AU

C0-

92, d

ay 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

2).

Rijk

en(2

011-

2)Th

aila

nd(J

une

2008

-D

ec 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht<

25%

) with

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

24 p

regn

ant

wom

en24

non

-

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,

Bas

ed o

n th

esa

me

clin

ical

stud

y as



5

Ben

jam

in(2

015)

Papu

a N

ewG

uine

e (n

otre

port

ed)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A>1

4wks

)an

d ag

e-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

with

mal

aria

infe

ctio

n.

Gro

up 1

DH

A-P

PQ(7

/58

mg/

kgp.

o. q

.d. f

or3

days

)

Gro

up 2

PPQ

(128

0mg

p.o.

q.d

. for

3 da

ys) +

SP

(25m

g/kg

once

)

32 p

regn

ant

wom

en33

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

MTT

, NN

,C

L/F,

Vc/

F,Q

/F, V

p/F,

t 1/2,

AU

C0-

∞.

Ada

m(2

012)

Suda

n(A

ug20

07-F

eb20

08)

Clin

ical

trail

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

(afte

rdo

se 1

, 2an

d 3)

, Tm

ax

(afte

r dos

e1,

2 a

nd 3

),C

L/F,

V/F

,T 1

/2, A

UC

0-la

st, A

UC

0-∞

, AU

C-

∞/d

ose,

AU

C0-

24,

AU

C24

-48,

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Hog

lund

(201

2).

AU

C48

-72,

AU

C72

-∞,

day

7 an

d 14

conc

entra

tion.

Hog

lund

(201

2)Su

dan

(Aug

2007

-Feb

2008

)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(EG

A 1

5-40

wks

)w

ith u

ncom

plic

ated

P.fa

lcip

arum

mal

aria

and

Hb>

7g/d

L. &

age

-and

wei

ght-m

atch

ed n

on-

preg

nant

wom

en w

ithun

com

plic

ated

P. fa

lcip

arum

mal

aria

.

DH

A-P

PQ(2

.4/2

0m

g/kg

q.d

.fo

r 3 d

ays)

12 p

regn

ant

wom

en12

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,t 1/

2, A

UC

48-9

0,A

UC

0-90

,da

y 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Ada

m (2

012)

.

Tarn

ing

(201

2-1)

Thai

land

(Jun

e 20

08-

Dec

200

8)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht>

25%

) with

unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

q.d.

for 3

days

)

24 p

regn

ant

wom

en24

non

-pr

egna

ntw

omen

Com

partm

ent

al a

naly

sis

Cm

ax, T

max

,C

L/F,

V/F

,t1

/2, A

UC

0-24

, AU

C0-

92, d

ay 7

and

28co

ncen

tratio

n.

Bas

ed o

n th

esa

me

clin

ical

stud

y as

Rijk

en (2

011-

2).

Rijk

en(2

011-

2)Th

aila

nd(J

une

2008

-D

ec 2

008)

Clin

ical

trial

Preg

nant

wom

en in

seco

ndan

d th

ird tr

imes

ter o

fpr

egna

ncy

(Ht<

25%

) with

DH

A-P

PQ(6

.4/5

1.2

mg/

kg p

.o.

24 p

regn

ant

wom

en24

non

-

Non

com

part

men

tal

anal

ysis

Tota

l dos

e,C

max

,C

max

/dos

e,

Bas

ed o

n th

esa

me

clin

ical

stud

y as



unco

mpl

icat

edP.

falc

ipar

umm

alar

ia &

mat

ched

non

-pr

egna

nt w

omen

with

P.fa

lcip

arum

mal

aria

.

q.d.

for 3

days

)pr

egna

ntw

omen

CL/

F, V

/F,

t 1/2,

AU

C0-

last

, AU

C0-

∞, A

UC

0-∞

/dos

e,A

UC

0-24

,A

UC

24-4

8,A

UC

48-7

2,A

UC

72-∞

,da

y 7,

14

and

28co

ncen

tratio

n.

Tarn

ing

2012

-1.

173

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