REVIEW

Educational paperDo we need neonatal clinical pharmacologists?

Karel Allegaert & Jean Paul Langhendries &

John N. van den Anker

Received: 28 February 2012 /Accepted: 28 March 2012 /Published online: 16 May 2012# Springer-Verlag 2012

Abstract Effective and safe drug administration in younginfants should be based on integrated knowledge concerningthe evolving physiological characteristics of the infant whowill receive the drug and the pharmacokinetic and pharma-codynamic characteristics of a given drug. Consequently,clinical pharmacology in neonates is as dynamic and diverseas the neonates we are entitled to take care of. Even morethan median estimates, covariates of variability within thepopulation are of clinical relevance. We aim to illustrate thecomplexity and the need for neonatal clinical pharmacologybased on the gap between current and likely best clinical practicefor two commonly administered compounds (aminoglycosides

for infection and ibuprofen for patent ductus arteriosus) and onenew compound (bevacizumab, to treat threshold retinopathy ofprematurity). Progression has been made to render pharmacoki-netic studies child size, e.g., low volume samples, optimal studydesign, and population pharmacokinetics. Challenges to furtherimprove clinical pharmacology in neonates include, whenappropriate, the validation of off-patent drug dosing regimensand of infant-tailored formulations. Knowledge integration,i.e., the use of available data to improve current drug use and topredict pharmacokinetics/pharmacodynamics for similar com-pounds is needed. Development of clinical research networksis helpful to achieve these goals.

Keywords Pharmacodynamics . Pharmacokinetics .

Newborn . Clinical pharmacology . Ontogeny . Maturation

Introduction: neonatal pathophysiology is reflectedin neonatal clinical pharmacology

Drug dosing in young infants should be based on integratedknowledge concerning the specific diseases to be treated,the physiological characteristics of the infant receiving thedrug, and the pharmacokinetic and pharmacodynamicparameters of this drug [1, 24, 43]. When we consider thesephysiological changes and the subsequent variability inphysiological characteristics, we should be aware that mat-urational changes in physiology are most prominent in earlyinfancy [15]. If we focus on weight changes to illustrate this,there is an initial decrease (6–12 %) in birth weight, with asubsequent increase of 50 % in the first 6 weeks of postnatallife. Moreover, weight doubles in the first 3–4 months toresult in a threefold higher weight at the end of infancy.Consequently, total energy requirements change dramaticallysince these requirements are the sum of energy expenditure

K. Allegaert (*)Neonatal Intensive Care Unit, Division of Woman and Child,University Hospitals Leuven,Herestraat 49,3000 Leuven, Belgiume-mail: karel.allegaert@uz.kuleuven.ac.be

J. P. LanghendriesCHC-Site St Vincent, NICU,Rue François Lefèbvre 207,Liege-Rocourt, Belgium

J. N. van den AnkerDivision of Pediatric Clinical Pharmacology,Children’s National Medical Center,Washington, D.C., USA

J. N. van den AnkerDepartments of Pediatrics, Pharmacology, Physiologyand Integrative Systems Biology, George WashingtonUniversity School of Medicine and Health Sciences,Washington, D.C., USA

J. N. van den AnkerIntensive Care, Erasmus MC-Sophia Children’s Hospital,Rotterdam, the Netherlands

Eur J Pediatr (2013) 172:429–435DOI 10.1007/s00431-012-1734-4

and energy deposition for growth [1, 24, 43]. These matura-tional physiological changes are further modulated by patho-physiological processes (e.g., perinatal asphyxia, cardiopathy,sepsis, renal failure, and patent ductus arteriosus) and treat-ment modalities (e.g., whole body cooling, extracorporealmembrane oxygenation (ECMO), or pharmacotherapy)applied. All these changes, both maturational (e.g., age andweight) and pathophysiological, are referred to as covariatesin clinical pharmacology.

The aim of administering any drug is to reach an effectivetreatment of a given disease while avoiding disproportionalside effects [16, 17]. Clinical pharmacology aims to predictdrug-specific (side) effects based on pharmacokinetics andpharmacodynamics. Pharmacokinetics (PK) describe therelationship between a drug concentration at a specific site(e.g., plasma and cerebrospinal fluids) and time (“what thebody does to the drug”). Pharmacodynamics (PD) describethe relationship between a drug concentration and (side)effects (“what the drug does to the body”) (Fig. 1). Theabove mentioned (patho)physiological changes in early neo-natal life result in extensive inter- and intraindividual vari-ability in PK and PD; in addition to median pharmacokineticestimates or outcome variables, the range and its covariatesare at least as crucial.

Pharmacokinetics in early infancy differ substantially fromchildren or adults as a result of physiology-related maturationin absorption, distribution, and subsequent elimination, eitherthrough metabolic elimination or through primary renal elim-ination (ADME, pharmacokinetics). Body composition, pro-tein binding, and compartment sizes change during infancy,all phases I (e.g., cytochromes) and II (e.g., glucuronidation)metabolic processes of drugs mature in an isoenzyme specificpattern, while renal function (glomerular filtration rate (GFR),tubular absorption/excretion) also displays age-dependentclearance [1, 15–17, 24, 43]. Age-dependent PD differencesare much less explored, but relate to age-dependent effects(e.g., caffeine to prevent neonatal apnea and lidocaine to treatneonatal seizures) or side effects (e.g., cerebral palsy related topostnatal steroids, ototoxicity related to aminoglycosides,furosemide, and noise pollution) [15–17, 21, 29].

The perception that the effects of a given drug are differ-ent in neonates often arises from the fact that the PK has notyet been adequately studied in neonates [1, 24, 43]. Thesame dose (e.g., per kilogram) in a neonate will result inanother concentration/time profile when compared to a childor adult. Consequently, we first have to get the dose right(PK, concentration/time profile) before we can search forpopulation-specific PD (concentration/effect profile) differ-ences. However, even after taking pharmacokinetic covariates(e.g., age and weight) into account, neonates often havealtered PD. In general, the pharmacological response dependson the drug binding to a drug receptor. Age-dependent varia-tions in receptor number, receptor affinity, or post receptor

activation processes could influence the drug response. Yet,information about the effect of receptor ontogeny on interac-tions between drugs and receptors and the consequence ofthese interactions is very limited in neonates. Gamma-aminobutyric acid (GABAA) and motilin receptor ontogenymay serve as illustrations [5, 22].

Due to developmental shifts in chloride membrane trans-porters, immature neurons have higher intracellular chlorideconcentrations. In the immature neuron, this results in achloride efflux when the GABAA receptor is activated in-stead of influx. This outward chloride flow results in cellularexcitation instead of inhibition. Pharmacological manipula-tion of this chloride shift by bumetanide decreases theintracellular chloride concentration and potentiates the anti-convulsant action of phenobarbital through GABAA inter-action. This chloride manipulation to switch from excitationto inhibition concept, i.e., the add-on effect of bumetanide inphenobarbital-resistant neonatal convulsions, is evaluated inthe NEMO trial [5]. Likewise, the intestinal motilin receptoralso displays age-dependent expression of intestinal motilin[22]. Since the motilin receptor only appears in older pre-term infants, prokinetic agents interacting with these motilinreceptors may not yet be effective in very preterm infants,only be partially useful in older preterm infants and moreeffective in full-term infants [22].

Despite the specific issues (PK/PD) of neonatal clinicalpharmacology, many drugs in neonates are still prescribedoff-label or remain unlicensed [8, 19, 21, 35]. This meansthat drugs are empirically dosed based on the extrapolationof observations in nonneonatal (i.e., children or adult) pop-ulations [2, 3, 11]. Off-label use, hereby, signifies the use ofa drug in situations not covered by the product license. Thismay relate to age, dosage, frequency or route of administra-tion, or due to extemporaneous formulation [8, 19, 21, 35].Although off-label use is already common in ambulatorypediatrics (30 %), it is most prominent in neonatal (90 %)intensive care [8, 19, 21]. All stakeholders involved (e.g.,pediatricians, policy makers, industry, and parents) need tobe aware that such “daily practice” and invalidated off-labeluse of drugs may have important negative effects; newbornsmay receive ineffective doses of potentially effective med-icines or may be harmed by medicines that might not beappropriate for their conditions. However, for some drugs,like aminoglycosides, these off-label dosing regimens haveundergone extensive validation [1, 10, 12, 13, 20, 26, 28,31, 32, 34, 37, 44, 45].

In this paper, we aim to illustrate the complexity and theneed of neonatal clinical pharmacology (PK/PD) based onthe gap between current and best clinical practice for twocommonly administered compounds (aminoglycosides forneonatal infection and ibuprofen for patent ductus arteriosus)and one new emerging compound (bevacizumab for thresholdretinopathy of prematurity).

430 Eur J Pediatr (2013) 172:429–435

Anti-infective drugs, aminoglycosides as illustration

The combination of in vitro and in vivo bactericidal charac-teristics resulted in a classification of antibiotics accordingto their specific PK/PD relationship [12, 26, 31, 37]. Whenwe focus on bacterial growth inhibition or killing, a variableconcentration response depending on this classificationneeds to be considered. Minimal inhibitory concentration(MIC) values and the most effective strategy to aim forrelate to both the antibiotic and the pathogen (Fig. 1). Forinstance, maintaining the serum concentration of >4 timesthe MIC is the goal for beta-lactams, while reaching a peak/MIC ratio of >8 is applied for aminoglycosides [12, 26, 31,37]. Since this strategy is focused on the pathogen, the chal-lenge in neonates is to maximize these concepts to result in amore efficacious treatment in the context of their immaturedistribution and excretion pathways [12, 26, 31, 37]. Conse-quently, population-specific PK estimates and its covariates areof utmost importance to propose effective dosing regimens forantibiotics [2, 3, 10–12]. The translation of these concepts intoeffective prescription of aminoglycosides in neonates is furtherdiscussed as an illustration of the difficulties encountered totranslate these concepts to effective and safe use of antibioticsin neonates [10–13, 23, 26, 31, 32, 34, 37, 44, 45, 47].

Because the bactericidal activity of aminoglycosidesdepends on the peak concentration with a persisted bacteri-cidal effect after this peak decreased, extended intervaldosing regimens have been developed [10, 26, 44, 45]. Inessence, such extended interval regimens result in high peaklevels and improved adherence to appropriate trough con-centrations because of the extended time interval. Animal

studies and trials in older children and adults suggest that sucha “one pulse strategy” for aminoglycosides administration issuperior (identical efficacy, but less toxicity) to a multipledoses per day regimen [26, 31, 34]. This is commonlyachieved in children and adults with a once-daily administra-tion, while in neonates, the time interval between consecutivedoses may be longer. When developing “extended time”dosing guidelines for neonates, this means that both clearanceand distribution volume (peak level) and its covariates need tobe considered. Consequently, the available knowledge onaminoglycoside PK (both clearance and distribution volume)in neonates needs to be integrated in the design of suchextended dosing guidelines.

Since aminoglycoside clearance reflects glomerular filtra-tion rate (GFR), neonatal aminoglycoside clearance is between1–5 % of adult clearance [10]. Within neonates, differences inaminoglycoside clearance can be expected to relate to ontogeny(e.g., gestational age, postnatal age, postmenstrual age, andweight) and disease characteristics (e.g., renal impairment dueto ibuprofen or perinatal asphyxia) [10, 11, 26]. Moreover, thedistribution volume for aminoglycosides is higher (liter perkilogram) in (pre)term neonates because of the higher extracel-lular water content [1, 10, 24]. While the lower eliminationclearance necessitates a further extended dose interval to reacha safe trough level, the higher distribution volume necessitateshigher doses [31].

At present, there are observations suggesting that phar-macokinetic properties (peak, trough) of an extended doseinterval for aminoglycosides are superior to “multiple dailydoses” since higher peak levels while avoiding toxic troughlevels are observed [31, 34]. However, this superiorityshould be balanced with the feasibility to introduce morecomplex dosing guidelines in our daily clinical practice[22, 32, 34, 37]. As recently suggested for gentamicin inneonates, these more complex dosing guidelines result in ahigher incidence of dosing errors [22, 32, 34, 37]. Thesedosing errors also relate to the multiple drug manipulationsneeded before the prescribed dose can be administered [36].

Pharmacodynamics and safety of antibiotics are in partunrelated to age (e.g., bacterial resistance), while otheraspects (nephro- and ototoxicity, colonizing intestinalmicrobiota) display infancy-specific patterns that may beeither protective or make this population more vulnerable[12, 13, 17, 20, 25, 28, 29, 31, 44, 45, 47]. The link betweentoxicity and high trough aminoglycosides levels is based onhistorical case series, when extended interval dosing regi-mens for aminoglycosides were not yet implemented, andrelates to the median concentration, the total dose, and thelength of treatment [13, 25, 27]. Megalin, a low-densitylipoprotein receptor in the renal proximal tubule and in thelabyrinth epithelium, is involved in aminoglycoside accumu-lation and toxicity [20, 28]. Since aminoglycoside binding toproximal renal tubular and cochlear cells is saturable,

Drug

Dose Conc Effect

Pharmacokinetics Pharmacodynamics

Absorption (side) effects, related to Distribution e.g. receptor expression Metabolism receptor activation Elimination intracellular signalling

AminoglycosidesDistribution volume reflects body composition Bacterial killing relates to peak concentrationClearance reflects renal clearance Ototoxicity relates to average /trough concentration

IbuprofenDistribution volume reflects body composition Relation ibuprofen/prostaglandins/PDA closureClearance by glucuronidation and renal clearance Relation ibuprofen/prostaglandins/renal impairment

BevacizumabAbsorption ‘despite’ deep compartment Impact on retinal and extraretinal angiogenesis

Fig. 1 Relationship between a drug concentration and (side) effects

Eur J Pediatr (2013) 172:429–435 431

strategies including the one pulse strategy and the shorteningin duration of aminoglycoside treatment when combined withother antibiotics likely increase the anti-infectious efficacyand decrease the risk of toxicities in neonates[20, 30, 33].Because renal tubular uptake capacity is not yet mature,nephrotoxicity related to accumulation by aminoglycoside isless pronounced in neonates when compared to other popula-tions [20, 28].

While the targets of antibiotics are pathogenic bacteria,other members of the microbiota are also affected by anti-biotics [25, 47]. This is a specific safety (PD) concern inneonates since it is a unique time in human life where amyriad of bacteria should colonize a sterile gut [25, 37, 47].The immune response at the submucosa intestinal level duringinfancy is a result of interactions between the infant and thisprogressive diversified intestinal microflora [47]. Interferen-ces with this progressive diversification of the microflora mayhave impact on the immune interaction. Consequently, im-mune abnormalities in later life may be due to inadequatebacterial pressure on the intestinal mucosa in early infancy.Perinatal exposure to antibiotics, including aminoglycosides,may modulate this microbiota and is a population-specific,long-term outcome variable [25, 37, 47].

Patent ductus arteriosus

In fetal life, the patent ductus arteriosus (PDA) divertsplacental oxygenated blood from the pulmonary artery intothe fetal aorta. After birth, modifications in prostaglandins,its receptors, and the postnatal increase in arterial oxygentension results in muscular constriction with subsequentanatomic closure of the ductus [6, 14, 18, 30, 41, 46, 48].These processes (constriction and closure) may be delayedor even fail in preterm infants. Indomethacin and ibuprofenare both effective to induce PDA closure with minor differ-ences between both compounds in the incidence of necro-tizing enterocolitis or bronchopulmonary dysplasia [46].Besides PDA closure, there are no other short-term outcomebenefits. From a clinical pharmacology perspective (Fig. 1),we would like to make the point that integration of theavailable knowledge on PK and PD of ibuprofen has notyet been optimized [6, 14, 18, 30, 41, 46, 48].

First, there are data on ibuprofen PK and its covariatesand one dose-finding, continual reassessment study ofibuprofen in preterm neonates with PDA. However, thePK information on covariates (age, weight) has not yet beenintroduced in prospective studies—“one dose still seems tofit all neonates” [14, 18, 30].

Second, also the PD part of this drug needs further con-siderations, including issues related to both diagnosticaccuracy and long-term safety. In a recent analysis on thedefinitions of symptomatic PDA applied in prospective

studies, a variety of clinical signs (e.g., murmur and hyper-dynamic circulation) or echocardiographic markers (e.g.,diameter ductus arteriosus and left atrium to aorta ratio)emerged without much data on sensitivity or specificity ofthe different indicators [48]. More recently, some groupsintroduced plasma biomarkers as a more valid indicator forsymptomatic PDA. It is hereby striking that there wasextensive variability in cutoff values between the differentstudies since the cutoff values of N-terminal fragment ofpro-brain-type natriuretic peptide (NT-proBNP) varied withup to tenfold differences [6, 30, 48]. We claim that furtherevaluation of the impact of sample handling and validationof quantification methods are needed before such PDAbiomarkers can be introduced in clinical care. For the issueon long-term outcome, a recent paper describes a linkbetween ibuprofen exposure and reduction in renal nephro-genic zone width in a baboon model, which may suggestearly cessation of nephrogenesis following ibuprofen expo-sure [40]. We are unaware of any long-term outcome studiesfollowing neonatal ibuprofen exposure.

Bevacizumab for treatment of retinopathyof prematurity

As recently discussed in this journal, retinopathy of prema-turity (ROP) is a proliferative retinal vascular disease affect-ing the premature infant with an incompletely vascularizedretina [7]. The spectrum of ophthalmological findings variesfrom minimal sequelae without visual impairment to bilat-eral retinal detachment and total blindness. Over the pasttwo decades, major advances have been made in understand-ing the pathogenesis of ROP. Based on well-designed, collab-orative multicenter studies, primary and secondary prevention(oxygen, nutrition) strategies, surgical indications, and surgi-cal techniques (threshold ROP, laser surgery) have beenvalidated [7].

The most recent advances relate to the intraocular injectionof bevacizumab. The BEAT-ROP study provided the firstevidence for intraocular injection of bevacizumab being lessinvasive and as effective for zones I–II retinopathy of prema-turity, compared to primary laser surgery [4, 9, 38]. Obviously,there is a need for improvement since laser therapy is, inessence, an ablative surgery. From a clinical pharmacologyperspective, there are, however, some PK and PD issues thatneed further considerations. First, although bevacizumab isinjected in a deep compartment (the eye), this compound stillappears in the general circulation [38]. This results in adecrease in serum vascular endothelial growth factor (VEGF),while we have to realize that VEGF is a relevant driver ofmicroangiogenesis (e.g., the brain, lung, and kidney) [4, 9,38]. Second, the issue of long-term visual outcome has not yetbeen thoroughly addressed since the need for subsequent laser

432 Eur J Pediatr (2013) 172:429–435

surgery was the primary outcome variable, and not (long-term) visual outcome [4, 9, 38].

Discussion: on recent advances and future challenges

By describing some aspects of clinical pharmacology ofaminoglycosides, ibuprofen, and bevacizumab, we tried tomake the point that integration of the available knowledgeon PK and PD is needed to further improve drug-relatedclinical care and outcome in neonates. The obvious aim ofany prescription is effective treatment of a given diseasewhile avoiding disproportional side effects. However, in theabsence of PK and dose-finding studies, one can only spec-ulate which dose to use. Similarly, in the absence of data onthe relevant outcome variables (PD), one can still report onthe association of a given compound and an effect. Howev-er, this treatment may result in unknown side effects becausethey are not yet reported. We would like to refer to someknown neonatal drug “errors” to further illustrate this.

Inadvertent, i.e., extrapolated based on adult dosing,administration of chloramphenicol resulted in gray babysyndrome due to accumulation of chloramphenicol. Thisrelates to the reduced glucuronidation capacity in early life.This is not an issue of population-specific toxicity, butrelates to the reduced clearance capacity (PK) in neonates[1, 24]. Similarly, postnatal dexamethasone results in shorterventilation time, but does not reduce the incidence of bron-chopulmonary dysplasia and even results in an increasedincidence of cerebral palsy and impaired neurodevelopmentaloutcome. This relates to a population-specific vulnerability(PD) [39]. Unfortunately, it took many more years beforethese negative long-term outcome data became apparent sincethe positive short-term outcome (i.e., extubation) delayed theevaluation of the impact of dexamethasone on neurodevelop-mental outcome in former preterm neonates [39].

Since the implementation of the pediatric regulation inthe USA and the subsequent initiatives in Europe andthroughout the world, there is more clinical research in thefield of neonatal product development for new compounds.This increase does not only result in more challenges suchas how to perform these studies, but also creates opportuni-ties for population-tailored approaches in both pediatricproduct development and clinical research [33]. Concertedefforts to improve research tools for pharmacokinetics andpharmacodynamics will likely result not only in improveddrug therapy in infants, but will also be a potent driver tolearn more about developmental physiology of infancy. Thefeasibility of performing pharmacokinetic studies in neo-nates and infants improved with the introduction of tailoredsampling methods (e.g., saliva, dried spots blood, or urine)and more accurate quantification of metabolites in low-volume samples [27, 43]. More importantly, the analysis

of sparse, unbalanced datasets and the burden for eachindividual infant can be minimized through modeling andsimulation using nonlinear mixed effect methods or physio-logically based pharmacokinetic (PBPK) modeling [2, 3, 11].Population pharmacokinetic models can also be used in thedesign of studies and in the sampling strategy to obtain max-imal information with a limited burden for every individualinfant. It permits the exploration of the influence of differentcovariates such as body weight and age to explain the vari-ability in drug concentration and/or response [2, 3, 11, 27, 43].We refer the interested reader to some reviews on aspects ofpopulation PK in pediatrics [2, 3, 11].

However, we still fail to a certain extent to validate suchmodels in the clinical setting, including aspects like feasi-bility. We, hereby, also refer to the aminoglycoside topic asan illustration that complex dosing guidelines itself result innew problems [22, 32, 34, 37]. Moreover, the ongoingresearch for new compounds and the availability of tailoredresearch tools still leave us with challenges to further improvethe clinical care in neonates, including prioritization andimplementation [27, 42, 43].

Clinicians need to be aware of the fact that an importantbulk of currently prescribed, off-patent drugs in neonateshave not yet appropriately been evaluated in neonates despitethe availability of specific incentives (e.g., paediatric usemarketing authorization (PUMA)) [8, 16, 17, 19, 21, 33,43]. The Neonatal Clinical Studies Group (CSG) of the Med-icines for Children Research Network (MCRN) undertook a2-week prospective survey to establish which medicines areused in neonatal units in the UK, how many babies arereceiving them, and what clinicians considered importantissues for future research [42]. Treatment of chronic lungdisease and of PDA and vitamin supplements turned out tobe high on their priority list. Such a research agenda forneonatal medicines can subsequently be considered in thedevelopment of priority lists of medicines by the competentauthorities. The project called treat infections in neonates(TINN) is an illustration of such a research initiative basedon a priority list [21, 43]. Besides compound- (e.g., flucona-zole, micafungin, and azithromycin) specific results, suchinitiatives also result in network of units with experience inevaluating drugs in neonates. An additional important initia-tive called Global Research in Paediatrics (GRIP) will focuson international pediatric clinical pharmacology training andaims to facilitate the development and safe use of medicine inchildren through training and education [19, 21, 43].

In summary, clinical pharmacological research in neo-nates should be as dynamic and diverse as the neonates weare entitled to take care for. Even more important than themedian estimates, we have to search for covariates of vari-ability within this population. Progression has been made torender studies child size (e.g., low-volume samples, popu-lation PK, and optimal study design). Challenges to further

Eur J Pediatr (2013) 172:429–435 433

improve clinical pharmacology in neonates include, whenappropriated, the validation of off-patent drug dosing regi-mens and of infant-tailored formulations. Knowledge inte-gration, i.e., the use of available data to improve currentdrug use and to predict pharmacokinetics/pharmacodynam-ics for similar compounds is needed. Development of clin-ical research networks should be helpful to achieve thesegoals. At least, we hope that we, hereby, were able toconvince the readers that neonatal clinical pharmacology isa relevant discipline.

Acknowledgments Karel Allegaert is supported by the Fund forScientific Research, Flanders (Belgium) (F.W.O. Vlaanderen) by aFundamental Clinical Investigatorship (1800209N) and a researchgrant (1506409N). Jean-Paul Langhendries is supported partly by theFP5 grants QLRT-2001-00389 and QKL1-CT-2002-30582, the FP6grant EARNEST Food-CT-2005-007036, and FP7 grants TINN(223614) and TINN2 (260908). Johannes van den Anker is supportedin par t by NIH grants (R01HD060543, K24DA027992,R01HD048689, U54HD071601) and FP7 grants TINN (223614),TINN2 (260908), and NEUROSIS (223060).

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