Pharmacokinetics of new molecular entity (NME) and new ...hktmc.com.cn/ChineseMedia/Magazine/Medicine/ajdmpk... · drugs (20 new molecular entity drugs and 6 new biologic license

Gao J and LiuCX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(2):93-121

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Asian Journal of

Pharmacodynamics and Pharmacokinetics

ISSN 1608-2281

CSSX-CPS

Pharmacokinetics of new molecular entity (NME) and new biologic license application (BLA) approvals in 2009 Jack Gao1, Chang-Xiao Liu2* 1 Bio-Research Lab, Novapharm Ltd., 10 O’Halloran Cres, Toronto, Ontario, M1V 2C3, Canada 2 Tianjin Research Center for New Drug Evaluation, Tianjin Institute of Pharmaceutical Research, 308 An-Shan West Road, Tianjin 300193, China

Abstract According to FDA’s information, there are 26 new drugs (20 new molecular entity drugs and 6 new biologic license application approvals) approved in Calendar Year of 2009. In this review, the aim is to provide an overview of the pharmacokinetics of these new molecular entity and new biologic license application approvals.

Key words review, pharmacokinetics, new molecular entity approvals, new biologic license application approvals

Article history Received 30 March 2010; Accepted 12 May 2010 Publication data Pages: 29; Tables: 3; Figures: 1; References: 99; Paper ID 1608-2281-2010-10020089-29 *Corresponding author Professor Chang-Xiao Liu, Research Center for New Drug Evaluation, Tianjin State Key

Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. E-mail: [email protected]

Introduction

According to FDA’s information, there are 26 new

drugs (20 new molecular entity drugs and 6 new biologic license application approvals) approved in Calendar Year of 2009 (see Table 1 and 2). Compared with 2008[1], the total number of new drugs is more than three drugs in 2009. In 19 new molecular entity drugs, there are 5 cardiovascular system drugs, 4 nervous system drugs, 3 anti-infective drugs, 2 anti-cancer drugs, 2 blood system drugs, and 4 other drugs.

New biologic license application (BLA) approvals

1 Ecallantide Ecallantide is a 60 amino acid recombinant

protein expressed in Pichia pastoris yeasts. It was found in earlier studies to be a highly specific and effective inhibitor of the kallikrein cascade, thereby decreasing generation and accumulation of bradykinin during an acute attack[2] Ecallantide 30 mg was administered subcutaneously to patients above age 10 for all types of attacks. Assessment of the effect was by a combined outcome score – a composite measure specific for HAE, patient reported outcomes, mean symptom complex severity, and time to significant improvement on a scale of 1 to 4. Safety parameters included laboratory, electrocardiographic, adverse-event recordings and measurement of immunoglobulin E and non-IgE antibodies to ecallantide and P. pastoris.


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Table 1. New molecular entity approvals in 2009 Proprietary name Established name Applicant Indication 1 Savella Tablets Milnacipra HCl Tablets Cypress Bioscience Inc. Treatment of fibromyalgia

syndrome 2 Uloric Tablets Febuxostat

Takeda Pharmaceuticals North America Inc.

Management of hyperuricemia in patients with gout

3 Affenitor Everolimus

Novartis Pharmaceuticals Corp.

Treatment of advanced renal cell carcinoma

4 Coartem

Artemetheer 20 mg, Lumefantrine 120 mg


Treatment of infections due to Plasmodium falciparum or mixed infections including P. falciparum

5 Ulesfia Benzyl alcohol Sciele Pharma Inc. Indicated for pts infected with Pediculus humanus capitas (Head lice) of the scalp hair

6 Fanapt Iloperidone Vanda Pharmaceuticals Inc.

Schizophrenia

7 Samsca

Tolvaptan 15 mg/ 30 mg Tablets

Otsuka America Pharmaceutical Inc.

Treatment of clinically significant hypervolemic and euvolemic hyponatremia

8 Besifloxacin HCl Besifloxacin Bausch and Lomb Inc. Bacterial conjunctivitis 9 Multaq

Dronedarone HCl Sanofi Aventis US Inc. Reduction in hospitalization or

death in patients with a history of or current atrial fibrillation or atrial flutter

10 Effient Prasugrel Eli Lilly and Co. Acute coronary syndrome 11 Onglyza

Saxaglipitin Bristol myers Squibb

Co. Type 2 diabertes mellitus

12 Livlo tablets Pitavastatin

Kowa Research Institute Inc.

For cholesterol treatment

13 Saphris

Asenapine

Organon USA Inc.

Treatment of schizophrenia treatment of acute manic or mixed episodes associated with bipolar Division

14 Sabril

Vigabatrin

Lundbeck Inc.

Indicated as add therapy for the treatment of complex partial seizures with or without secondary generalization in adults

15 Bepotastine

Bepotastine Besilate ophthalmic solution

Ista Pharmaceuticals

Treatment of ocularitching associated with allergic conunctivittis

16 Telavancin

Telavancin Theravace Inc.

Complacated skin and skin-structure infections

17 Folotyn

Pralatrexate injection 20 mg/1ml, 40mg/2ml

Allos Therapeutics Inc.

Relapsed or refractory peripheral T-cell lymphoma

18 Votrient Tablets

Pazopanib Tablets

GlaxoSmithklineL

Treatment of patients with advanced renal cell carcinoma

19 Istodax

Romidepsin Gloucester Pharmaceuticals Inc.

Treatment of cutanous T-cell lymphoma in patients who have received at least oneprios systemic therapy.


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Table 2. New biologic license application (BLA) approvals Propritary name Proper name Applicant Indication 1 Golimumab

Simponi

Centocor Ortho Biotech Inc.

New BLA for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

2 Abobotulinumtoxina Dysport

Ipsen Biopharm Limited.

Treatment of cervical dystomia (Spasmodic torticollis)

3 Canakinumab

Ilaris


Treatment of cryorin associated periodic syndrome (CAPS) in pediatrics and adults

4 Ustekinumab

Stelara

Centocor Ortho Biotech Inc.

Treatment of psoriasis

5 Ofatumumab

Arzerra

Glaxo Group Limited D/B/A Glaxosmithkiline

Treatment of patients with chronic lymphocytic leukemia cell refractory to fludarabine and alemtuzumab

6 Ecallantide

Kalbitor

Dyax Corp. Treatment of hereditary angioedema

Table 3. Comparison of new molecular entity drugs in 2008 and 2009

Year 2008 2009 Number of new molecular entity drugs 22 19 Nervous system drugs 5 4 Blood and hemopoietic system drugs 4 2 Anti-infective drugs 3 3 Digestive system drugs 2 Cardiovascular system drugs 2 5 Contrast agents 2 Anti-cancer drug 1 2 Other drugs 3 3

In a study[3], Reshef et al recruited seven HAE

patients, but only two (12 and 16 years old) were randomized during an acute attack, since the study in Israel and Europe was prematurely terminated earlier than scheduled. Results of the studies in the USA and Europe, including isolated reports on anaphylactic reactions (sensitization via anti-Pichia IgE antibodies), has been published elsewhere. [4,5]

2 Golimumab Golimumab is a fully human antitumor

necrosis factor-α (TNF-α) monoclonal antibody that is being developed for intravenous and subcutaneous administration. In the pharmacokinetics (PK) and safety of the intravenous formulation of golimumab, 36 adult subjects with rheumatoid arthritis were randomly assigned to

receive a single infusion of placebo or golimumab (0.1, 0.3, 1, 3, 6, or 10 mg·kg-1). Serum concentrations of golimumab were determined using a validated ELISA method. In addition to the noncompartmental analysis and compartmental modeling, a population pharmacokinetics analysis using NONMEM was also conducted. Both the maximum serum concentration and the area under the serum concentration time curve AUC appeared to increase in a dose-proportional manner. The median t1/2 ranged from 7 to 20 days. A 2-compartment population PK model adequately described the PK of golimumab. The following PK parameters (typical value % coefficient of variation) were estimated from the population PK model: (CL: 0.40 L·d-1), (Vd in the Vc: 3.07 L), intercompartmental clearance (Q: 0.42 L·d-1), and


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(Vd in the peripheral compartment Vp: 3.68 L). Interindividual variability of the PK parameters was quantified as CL 44.3%, Vc 25.5%, Q 44.6%, and Vp 44.6%. Residual variability was estimated to be 15.0%. Body weight was found to be an important covariate on Vc. Golimumab was generally well tolerated. The PK of golimumab appeared to be linear over the dose range evaluated in this study. [6]

In a phase 1 clinical study the single-dose PK and safety of subcutaneous golimumab were evaluated in healthy Japanese and Caucasian subjects. All 51 subjects (24 Japanese, 27 Caucasian) were included in the safety analysis; 47 completed the study and were included in the PK analysis. The PK of golimumab was comparable in both race groups. Peak concentrations were observed ~4 to 6 days after administration. No significant differences in exposure or mean t1/2 (11-13 days) were observed between Japanese and Caucasian subjects at the same dose level. Regardless of race, serum golimumab exposure increased with increasing dose. Mean apparent clearance ranged from 12 to 19 mL·kg-1·d-1). Mean apparent Vd (224-262 mL·kg-1) remained constant with an increase in dose. No antibodies to golimumab were detected. Single subcutaneous injections of golimumab 50 mg or 100 mg were generally well tolerated in these healthy male Japanese and Caucasian subjects. [7]

The population PK of subcutaneously administered golimumab (50 mg or 100 mg every 4 weeks) were characterized in patients with active psoriatic arthritis, a randomized, double-blind, placebo-controlled, phase III study. A total of 2029 serum golimumab concentrations from 337 patients were analyzed using NONMEM. A one- compartment PK model with first-order absorption and elimination was chosen to describe the observed concentration-time data. The golimumab PK parameters were as follows: apparent CL 1.38 ± 0.04 L·d-1, apparent Vd 24.9 ± 1.04 L, and Ka 0.908 ± 0.121 per day. Body weight, antibody-to- golimumab status, baseline C-reactive protein level, and smoking status were identified as significant covariates on apparent clearance. Body weight was also a significant covariate on apparent volume of distribution. None of the concomitant medications examined were significant covariates on apparent clearance, although the median trough golimumab

concentration in patients receiving methotrexate was higher than for those not receiving methotrexate. These significant covariates account for part of the variability in systemic exposure to golimumab observed in patients with PsA. [8]

3 Ofatumumab Ofatumumab is a unique monoclonal antibody

that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/ chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. It is an anti-CD20 human mAb, for the potential intravenous treatment of non-Hodgkin's lymphoma and autoimmune diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Phase I and II clinical trials have been completed in patients with chronic lymphocytic leukemia (CLL), rituximab-refractory follicular lymphoma (FL) and RA. At the time of publication ofatumumab was undergoing a phase II clinical trial in patients with diffuse large B-cell lymphoma and phase III clinical trials in patients with B-cell CLL (B-CLL) in which fludarabine and alemtuzumab treatments have failed and in patients with rituximab- refractory FL. Ofatumumab was also undergoing phase II clinical trials as a combination therapy for previously untreated patients with FL in combination with cyclophosphamide, adriamycin, vincristine, and prednisone and in combination with fludarabine and cyclophosphamide for the treatment of B-CLL. In addition, two phase III clinical trials to assess patients who have an inadequate response to methotrexate and TNFalpha therapy were ongoing for patients with RA, and a phase II clinical trial to investigate the effects of repeated doses of ofatumumab was recruiting patients with RA from a previous trial on ofatumumab. A phase I/II clinical trial of ofatumumab in relapsing-remitting MS was expected to commence in 2008. [9]

In a phase I/II trial evaluating safety and efficacy of ofatumumab in relapsed or refractory


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follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL.[10] Bleeker et al evaluated the dose requirements for sustained in vivo activity of ofatumumab, a human anti-CD20 antibody under development for the treatment of B cell-mediated diseases. In a mouse xenograft model, a single dose, resulting in an initial plasma antibody concentration of 5 µg·mL-1, which was expected to result in full target saturation, effectively inhibited human B-cell tumor development. Tumor growth resumed when plasma concentrations dropped below levels that are expected to result in half-maximal saturation. Notably, tumor load significantly impacted antibody PK. In monkeys, initial depletion of circulating and tissue residing B cells required relatively high-dose levels. Re-population of B-cell compartments, however, only became detectable when of atumumab levels dropped below 10 µg·mL-1. Researchers concluded that, once saturation of CD20 throughout the body has been reached by high initial dosing, plasma concentrations that maintain target saturation on circulating cells (5-10 µg·mL-1) are probably sufficient for sustained biological activity. These observations may provide a rationale for establishing dosing schedules for maintenance immunotherapy following initial depletion of CD20 positive (tumor) cells. [11]

4 Abobotulinumtoxin A AbotulinumtoxinA is used for the treatment of

cervical dystomia (Spasmodic torticollis) and has broadened the neurotoxin market and provides new therapeutic alternatives to practitioners. The introduction of this product raises questions about how to best use it. In this supplement, Hexsel et al addressed critical similarities and differences between abotulinumtoxinA (Botox and Dysport). The authors also provide practical guidelines for the use of Dysport based on clinical experience and peer-reviewed, published clinical trials. In the authors' opinion, Botox and Dysport can be used for similar "on-" and "off-label" applications. Judicious use of either product requires an understanding of how the two products differ in order to avoid side effects and achieve optimal results.[12]

To ensure optimal treatment outcomes with AbobotulinumtoxinA (BoNTA), it is crucial for injectors to adopt proper methods of reconstitution and injection, which can be acquired through training. Rzany et al reviewed the method of reconstitution for BoNTA, as well as the injection dose, points and techniques for glabellar line treatment. Rzany et al also review the efficacy and safety results of BoNTA demonstrated in 11 clinical studies, most of which were randomized, double-blind and placebo-controlled. The studies included assessments after single injections as well as after up to 6 repeated treatment sessions. They summarized the clinical efficacy results, which include the responder rate 1 month post-injection, onset of response and duration of action, as well as safety results, which include incidence of treatment-emergent adverse events and specifically eyelid ptosis. The efficacy and safety profiles reported here are unique to BoNTA and cannot be generalized to other BoNTA products.[13]


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asenapine

Benzyl alcohol bepotastine

besifloxacin

Coartor

drodarone

everolimus

febuxostat iloperidone

minacipran

pazopanib

pitavastatin

prasugrel

romidepsin

saxagliptin

vigabatrin

telavancin

tolvaptan

Fig 1. Chemical structures of new molecular entity approvals


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The focus was on clinical medicine and aesthetic trials. Several studies with the Cosmetic formulation of abobotulinumtoxinA (BoNTA) included relapse rates, defined conservatively as return to baseline levels of line severity for two consecutive visits approximately 30 days apart (at repose and maximum contraction). In these studies, duration of effect ranged from 3 to 5 months in female patients and from 4 to 6 months in male patients. Individual patients had longer durations of response. Across all studies providing relapse rates, most patients relapsed by 6 months. In studies assessing patient satisfaction, satisfaction remained high throughout the duration of the studies (approximately 4 months). With the BoNTA retreatment intervals were estimated at a mean of 3.9 months (median = 3.3 months). These results were consistent with responder rates from another abobotulinumtoxinA formulation (Dysport) study in which the active treatment differed from placebo at 3 but not 4 months. In conclusion, patients can expect treatments to last > or =3 months but often as many as 4-5 months depending on the facial area, dose, and formulation. Additional research should help clarify the impact of age, baseline rhytid severity, patient sex, repeated treatments, and combination treatment on longevity of effect.[14]

Using quantitative analysis of regional paralysis produced by local injections into the gastrocnemius muscles of mice, prior studies estimated the potency ratio between Dysport and BOTOX to be 4.2 to 1. In a single-blind, randomized comparison study of Dysport and BOTOX in 91 patients with blepharospasm or hemifacial spasm, it was found that 4:1 dose ratio produced similar benefits. A similar 4:1 Dysport: BOTOX ratio was found to produce equivalent beneficial effects in a double-blind study in patients with blepharospasm, but the frequency of side effects, particularly of ptosis, was lower in the BOTOX group. In a study of 73 patients with cervical dystonia treated either with Dysport or BOTOX, it was concluded that a 3:1 ratio provides equivalent results. But a recent study concluded that the appropriate conversion factor between BOTOX and Dysport is less than 3. Therefore, there is some controversy about the relative potencies of the two preparations, with one

study proposing that 1 unit of BOTOX corresponds to 1 unit of Dysport.[15]

5 Ustekinumab Ustekinumab, a human immunoglobulin G1

kappa (IgG1k) monoclonal antibody that binds with high affinity to human interleukin-12 and interleukin-23, has demonstrated efficacy in patients with psoriasis.[16]

In a phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18-65 years, were eligible to be assigned equally (by a central randomization procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that received placebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded. Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis.[17]

The population PK of ustekinumab is characterized in patients with moderate to severe


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plaque psoriasis in 2 Phase III studies. Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent volume of distribution, and absorption rate constant from the final covariate model are 0.465 L.d-1 (2.0%), 15.7 L (2.0%), and 0.354 d-1 (16.2%), respectively. Theinter individual variabilities for apparent clearance and apparent volume of distribution are 41.0% and 33.2%, respectively. Of the factors evaluated in this analysis, body weight, diabetes, and positive immune response are important covariates affecting the apparent clearance and/or apparent volume of distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.[18] Zhou et al carried out the population-based exposure-efficacy modeling of ustekinumab in patients. Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg. Disease severity was assessed using Psoriasis Area and Severity Index (PASI) scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic (PD) response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model. None of the covariate factors evaluated in demographics, baseline disease characteristics, comorbidities significantly contributed to the between-subject variability in the PD parameters. The developed model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate to severe plaque psoriasis. A robust exposure-response relationship has been confirmed for ustekinumab in psoriasis.[19]

In two large, phase III trials in patients with moderate to severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as two injections 4 weeks apart) than placebo recipients achieved a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 weeks. Other efficacy

measures, including the physician's global assessment of clinical response at week 12, also favored ustekinumab over placebo. Psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks. In a phase II trial in patients with active plaque psoriasis and psoriatic arthritis, signs and symptoms of arthritis and psoriatic symptom control were improved to a greater extent with ustekinumab than with placebo at 12 weeks, based on the proportion of patients achieving a 20% improvement in Rheumatology response criteria (arthritis) or PASI 75 (skin symptoms). Health- related quality of life, assessed using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index, was improved to a significantly greater extent with ustekinumab than with placebo at week 12. Subcutaneous ustekinumab was generally well tolerated in clinical trials, with most treatment- emergent adverse events being of mild severity.[20]

Scanlon et al systematically reviewed the pharmacology, PK clinical efficacy, and safety profile of ustekinumab to inform pharmacists and other healthcare professionals of this new biologic therapy for psoriasis. All available studies relevant to the pharmacology, PK, and clinical safety/ efficacy of ustekinumab for the treatment of psoriasis were included, with preference for human data. These efficacy results were reproduced in the ACCEPT trial, demonstrating superiority of ustekinumab to etanercept. The frequency of adverse events was similar between ustekinumab and placebo; common adverse events reported included nasopharyngitis, upper respiratory tract infection, headache, arthralgia, cough, and injection site reactions. Phase III studies indicate that the optimal dosing appears to be 45 mg for patients weighing less than 100 kg or 90 mg for patients weighing more than 100 kg, with both doses administered subcutaneously. In these studies, the second dose was given 4 weeks after the first and then every 8-12 weeks thereafter, based upon response. Therefore, they suggested that ustekinumab, a promising new therapy, reduces the extent and severity of psoriasis and well tolerated in clinical trials.[21]


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6 Canakinumab Canakinumab (ACZ-885) is a fully humanized

monoclonal antibody (mAb) specific for IL-1beta and is indicated for a wide range of inflammatory disorders including cryopyrin- associated periodic syndromes (CAPS).[22] Canakinumab is used for the treatment of familial cold auto-inflammatory syndrome and Muckle- Wells syndrome, which are inflammatory diseases related to CAPS. The drug is currently being evaluated for its potential in the treatment of rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis, chronic obstructive pulmonary disease, type 1 and 2 diabetes and ocular diseases. Clinical trials suggested that canakinumab is well-tolerated in most patients, and no serious adverse effects have been reported. The drug provides significant advantages over existing competitive therapies, including bimonthly administration and approved use in children.[23]

Early clinical trials have established the administration of canakinumab every 2 weeks to be safe and effective, offering a considerable advantage over the existing treatment with the human IL-1 receptor antagonist anakinra, which must be injected daily and which is often poorly tolerated by patients. In phase III clinical development of canakinumab was recently granted. The availability of more than one IL-1 targeting biological agent is undoubtedly advantageous, not only for patients and clinicians, but also for the elucidation of disease mechanisms.[24] New Molecular Entity Approvals

1 Romidepsin Romidepsin (depsipeptide) is a bicyclic

peptide isolated from Chromobacterium violaceum. Romidepsin has demonstrated potent antitumor activity against many human tumor cell lines and in various xenograft models, mainly via inhibition of histone deacetylase (HDAC). The acetylation status of histone proteins is important for modulation of gene expression and is highly controlled by the interplay between HDAC and histone acetyl- transfereases (HAT). Aberrant HDAC activity is believed to be a contributing factor to neoplastic transformation, having been identified in various cancers including leukemia, lymphoma, and solid

tumors HDAC inhibitors, a relatively new class of antitumor agents, restore the acetylation of histones and modulate the transcription of genes involved in cell growth, differentiation, and apoptosis. In addition, multiple cellular effects have been described through the increased acetylation of multiple non-histone proteins. It is not clear which among these effects is most critical for antitumor activity. Romidepsin is currently in phase II clinical trials for the treatment of T-cell lymphoma and advanced solid tumors.[23] Preclinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg·m2 depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by NCI criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression[25]. Byrd et al conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules.[26]

In the present study finished by Woo et al[27], they evaluated the relative contribution of polymorphisms in metabolizing enzymes and transporters of romidepsin to the pharmacokinetics. While romidepsin undergoes extensive metabolism by CYP3A4 and CYP3A5, their gene sequence variations did not affect romidepsin PK. A recent study showed that Caucasian patients carry a copy


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of both CYP3A4*1B and CYP3A5*1A. Of 75 Caucasians in our study there were only three individuals categorized into this group and their clearance did not differ from remaining patients. Studies have shown that variant alleles in ABCB1 alter protein folding, function and/or expression level in different types of tissues.[28,29] For example, the variant alleles at loci 2677 and 3435 of ABCB1 have been associated with lower expression of hepatic ABCB1[30]. Thus, it was hypothesized that polymorphisms in ABCB1 may result in reduced transport of romidepsin into bile, thereby resulting in decreased overall clearance. A tendency towards lower CL was seen in patients carrying ABCB1 2677 variant alleles, especially for individuals. Woo et al’s study presents a population PK model of romidepsin in patients with cutaneous or relapsed peripheral T-cell lymphoma who received a 4-hour infusion at the dose of 14 or 18 mg/m2 during their first treatment cycle. The disposition of romidepsin was well characterized by the two-compartment model with a linear elimination and exhibited moderate inter-patient variabilities. No statistically significant association was found between romidepsin PK and patient-specific covariates including polymorphic variations in CYP3A4/5, ABCB1, or SLCO1B3 in this population.[31]

2 Pralatrexate Pralatrexate (10-propargyl-10-deaza-amino-

pterin, PDX) is a novel antifolate designed to have high affinity for the reduced folate carrier type 1 (RFC-1). Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against TCL. The high affinity of pralatrexate for RFC-1 significantly improves its internalization into cells. Preclinical studies in models of B-cell lymphomas and TCL have demonstrated that pralatrexate demonstrates activity superior to traditional antifolates. Phase I studies have shown the dose-limiting toxicity to be stomatitis, which can be abrogated with folic acid and vitamin B12 supplementation. Early phase studies have shown marked activity across diverse panoply of TCL. Pralatrexate is an antifolate designed to be internalized more rapidly than other traditional antifolates. Preclinical studies have demonstrated its superiority to methotrexate, and

early phase I and II studies have shown marked activity across many poor-risk subtypes of TCL. Future studies are directed towards understanding the PK features of the drug, and expanding the population of patients with TCL and B-cell lymphomas.[31] As possible ATPases targeted by PBCD, all of these tumors expressed MRP-1, -4, and -7 genes, with expression of MRP-4 being greatest in each case. Four other MRP genes were expressed to a variable extent in some tumors but not others.[32] The therapeutic enhancement of PDX by PBCD was manifested as tumor regression, where PDX alone was only growth inhibitory (A549 NSCL tumor), or as a substantial increase (3-4-fold) in overall regression and/or number of complete regressions (Lewis and LX-1 lung, PC-3 and TSU-PR1 prostate,and MX-1 mammary tumors) compared to PDX alone. Also, only in the case of PDX with PBCD, a significant number of mice transplanted with LX-1 or MX-1 tumors that experienced complete regression did not have regrowth of their tumor. In view of these results, clinical trials of this therapeutic modality appear to be warranted, especially in the case of new more efficacious folate analogues that are also permeants for this canicular multispecific organic anion transporter /MRP-like plasma membrane ATPase.[33]

In a pralatrexate phase I study, preliminary evaluations of the PK of the drug were carried out. It is suggested that pralatrexate exposure AUC could be controlled with body size-based dosing and that pretreatment with folic acid and vitamin B12 might diminish the incidence and severity of mucositis. The study was amended, with revised dosing and vitamin B12 administration. Data from 47 patients were evaluated using NONMEM. Weight and methylmalonic acid (MMA) level were predictive of PK variability. AUC and MMA level were positively correlated with the risk of developing mucositis. A lower AUC schedule with vitamin B12 pretreatment may control mucositis without compromising efficacy. The application of modeling was a critical step in the development of pralatrexate, yielding important suggestions for dose, scheduling, and pretreatment modify- cations.[34]


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The antifolate pralatrexate demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum- tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. The starting dose was pralatrexate 40 mg/m2 intravenously and probenecid 70 mg/m2 intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate AUC, t1/2, and Cmax were determined in cycle 1. Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose- limiting with pralatrexate 40 mg/m2 and probenecid 233 mg/m2. Mean pralatrexate AUC and t1/2 increased with increasing doses of probenecid. No objective responses were seen. For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m2 and probenecid 140 mg/m2. Vitamin B12 and folate supplementation may allow for further dose escalation of pralatrexate and probenecid.[35]

Krung et al undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles. Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC.[36] A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.[37]

3 Telavancin

Telavancin is a lipoglycopeptide derivative of vancomycin. Similar to vancomycin, it demonstrates activity in vitro against a variety of Gram-positive pathogens, including but not limited to methicillin-resistant Staphylococccus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. The resulting activity in vitro is rapidly bactericidal and concentration dependent, with the ratio of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) as the best predictor of activity in animal models to date. In humans, telavancin exhibits a PK profile that permits once-daily intravenous administration. Doses of 7.5 and 10 mg·kg-1·d-1 have been studied in clinical trials. The need for dosage adjustments based on age, gender and obesity appear unnecessary. In addition, moderate hepatic impairment does not appreciably alter the PK of the drug.

Because telavancin is extensively cleared by the kidneys, dosage adjustments will be required in patients with moderate to severe renal impairment. Published phase II and III clinical trials have shown telavancin to be comparable to standard therapy for the treatment of complicated skin and soft tissue infections. Clinical trials in the treatment of S. aureus bacteremia and hospital-acquired pneumonia are under way. Adverse effects overall appear to be mild and reversible, with taste disturbance, foamy urine, headache, procedural site pain, nausea and vomiting being the most commonly reported. Renal toxicity was reported more frequently with telavancin than with vancomycin in two phase III clinical trials. Prolongation of the corrected QT (QTc) interval has been more common with telavancin than comparator agents, but no clinically significant electrocardiogram (ECG) changes or cardiac abnormalities have been observed to date.[36] The dynamics of the antimicrobial effect of telavancin against two strains of Staphylococcus aureus (methicillin susceptible and methicillin resistant) was studied in an in vitro kinetic model with simulated human pharmacokinetics. Also, static experiments were performed to determine the rate and extent of killing by telavancin in the presence and absence of human albumin and human serum. In the in vitro kinetic model regrowth was noted at 24 h for both strains when exposed to initial


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concentrations below 5 mg·L-1. At a target area under the curve/MIC ratio of 50 was observed at 6 to 8 h. Unlike most antibiotics, telavancin was able to kill both strains in a nongrowing phase.[37]

While the plasma PK has been described, the extent of the penetration of the drug into the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the penetration of telavancin into ELF. Plasma and ELF PK data were obtained from 20 healthy volunteers, and the PK samples were assayed by a validated liquid chromatography-tandem mass spectrometry technique. Monte Carlo simulation of 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the AUC for the drug in ELF (AUCELF) and for the free drug in plasma (free AUCplasma) from zero to infinity after a single dose. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations in plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. Themedian AUCELF/free AUCplasma penetration ratio was 0.73, and the 25th and 75th percentile value ratios were 0.43 and 1.24, respectively. In uninfected lung tissue, the median AUCELF is approximately 75% of the free AUCplasma.[38]

The steady-state PK parameters of telavancin was studied in a randomized, double-blind, parallel-group, gender-stratified, two-dose study, 79 adult subjects received three daily 60 min iv infusions of telavancin at 7.5 mg·kg-1 or 15 mg·kg-1. Following the day 3 telavancin dose (7.5 or 15 mg·kg-1), dose-proportional increases in mean peak plasma concentrations (Cmax, 88 versus 186 mg·L-1 for low and high doses, respectively) and total systemic exposures (AUC0-24, 599 versus 1282 mg.h·L-1 for low and high doses, respectively) were observed. Trough concentrations at steady state were 6 mg·L-1 at 7.5 mg·kg-1·d-1 and 16 mg·L-1 at 15 mg·kg-1·d-1. The elimination half-life was dose- independent; the ranged from 6.0 to 7.5 h for low and high doses, respectively. Approximately two-thirds of the total telavancin dose was excreted unchanged in urine over 48 h. PK parameters were similar in males and females. It showed that telavancin displayed linear plasma pharmaco-

kinetics over the dose range 7.5-15 mg·kg-1·d-1 and was primarily cleared via urinary excretion. No gender-related differences in the pharmacokinetic disposition of telavancin were observed. These data further characterize the PK profile of telavancin, a once-daily therapy targeted for the treatment of serious Gram-positive infections.[39]

4 Bepotastine ophthalmic solution Bepotastine is an ophthalmic H1-antihistamine

which is used for the treatment of ocularitching associated with allergic conunctivittis.[40] The antiallergic agent bepotastine besilate is a nonsedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-glycoprotein (P-gp) in the PK of bepotastine, intestinal absorption and brain penetration studies were performed. [14C]-Bepotastine transport in P-gp- overexpressed LLC-PK1 cells indicated that bepotastine was a substrate of P-gp. The affinity of bepotastine to P-gp estimated by ATPase activity assay was low, with a Km value of 1.25 mM. After i.v. administration, the brain/plasma free concentration ratio in mdr1-knockout mice was 3 times higher than that in wild-type mice. The in situ intestinal absorption studies of [14C]- bepotastine in rats showed a clear regional difference, showing highest permeability at the upper part of small intestine with a decreasing permeability in the descending part of small intestine. The apparent ka of [14C]-bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [14C]-bepotastine disappeared. The concentration dependence of ka of [14C]- bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 microM). Researchers suggested that bepotastine is a substrate for P-gp, and P-gp clearly limited the brain distribution of bepotastine, whereas the effect of P-gp on intestinal absorption of bepotastine was minimal, presumably because of high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane-permeable P-gp substrate fexofe- nadine.[41]


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5 Vigabatrin

Vigabatrin is an antiepileptic drug with a unique and novel mechanism of action, in the rat are sparse. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.[42] To investigate the PK interrelationship of vigabatrin in blood and the brain and to ascertain the relationship between brain extracellular vigabatrin concentrations and concurrent γ-aminobutyric acid (GABA) concentrations, Sprague- Dawley rats were implanted with a jugular vein catheter for blood sampling, and microdialysis probes in the frontal cortex and hippocampus for extracellular fluid (ECF) sampling. Vigabatrin was administered intraperitoneally at two doses (500 and 1,000 mg·kg-1), and blood and ECF were collected at timed intervals up to 8 h. Rats were freely moving and behaving. Vigabatrin (sera and ECF) and GABA (ECF) concentrations were measured with use of HPLC. The results showed that vigabatrin concentrations in blood rose linearly and dose-dependently, and vigabatrin rapidly appeared in the brain as evidenced by the detection of vigabatrin in the ECF of both the frontal cortex and hippocampus at time of first sampling (15 min). However, frontal cortex concentrations were twofold greater than those of the hippocampus. Furthermore, GABA concentrations increased five-fold in the frontal cortex but were unaffected in the hippocampus. In addition, GABA concentrations began to increase approximately 3 h after vigabatrin administration at a time when vigabatrin concentrations were in exponential decline. Vigabatrin distribution in the brain is region specific, with frontal cortex concentrations substantially greater than those seen in the hippocampus. Elevation of GABA concentrations did not reflect the concentration profile of vigabatrin but reflected its regional distribution.[43]

Vigabatrin was administered by intraperitonial injection at three different doses (250, 500 and 1000mg·kg-1) to Sprague-Dawley rats and blood and CSF collected at timed intervals up to 8 h. Vigabatrin concentrations in blood and CSF rose linearly and dose-dependently and Tmax was 0.4 and

1.0 h, respectively. Vigabatrin is not protein bound in serum and its elimination from serum (mean t1/2, 1.1-1.4 h) is rapid and dose-independent. The efflux of vigabatrin from CSF was significantly slower than that seen for serum (mean t1/2, 2.2-3.3h). The kinetics of vigabatrin is linear with rapid entry into CSF. However, although vigabatrin CSF kinetics parallel that seen in serum, CSF vigabatrin concentrations represent only 2% of concentrations seen in serum and do not reflect free drug concentrations in serum.[44] The newer antiepileptic drugs (AEDs), felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide, in general have more predictable PK than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their PK and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its PK variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the PK variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), PK variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs.[45]

6 Asenapine


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In August 2009, asenapine was approved by the US FDA for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults.[46] A double-blind 1-year trial of asenapine in patients with schizophrenia or schizoaffective disorder. Patients were randomized to asenapine (5 or 10 mg BID; n=913) or olanzapine (10-20 mg QD; n=312), and monitored regularly. Trial completion rates were 38% with asenapine, 57% with olanzapine; main reasons for discontinuation were withdrawal of consent (22%, 16%) and insufficient response (25%, 14%); fewer discontinuations were due to adverse events (6%, 7%). Mean weight gain was 0.9 kg with asenapine, 4.2 kg with olanzapine. Extrapyramidal symptoms reported as adverse events were more common with asenapine. Mean reductions in Positive and Negative Syndrome Scale (PANSS) total score with asenapine and olanzapine were -21.0 and -27.5; PANSS total score improved with both agents; the improvement was greater with olanzapine than with asenapine using last observations carried forward but not in an observed-case analysis.[47] Patients with schizophrenia may be at risk for drug-drug interactions (DDIs) with second generation antipsychotics. Some of the currently available second-generation antipsychotics have a higher potential for DDIs. Agents with a reduced liability for DDIs may be safer treatments as the systemic drug concentration is less likely to seriously increase/decrease when other medications are knowingly or inadvertently co-prescribed or hepatic problems and drug abuse is present.[48]

In a parallel design, patients received asenapine 5 mg twice daily (BID) for 10d followed by 10 mg BID for 6d, asenapine 15 mg BID for 10d) followed by 20 mg BID for 6d, quetiapine 375 mg BID (for assay sensitivity; 16d) or placebo (16d). Triplicate 12-lead electrocardiograms and concentration measurements were obtained on day -1, 1, 10, and 16 at 8 scheduled times on each day. At mean Cmax for all asenapine doses, the E-R model predicted that the mean QTcF increase was less than 5 milliseconds, the International Conference on Harmonisation established threshold for clinical concern. The model predicted a mean increase of 7 to 8 milliseconds for quetiapine. The corresponding

upper bounds of the 95% confidence intervals were 7.5 milliseconds and 11.2 milliseconds for asenapine and quetiapine, respectively.[49]

Modeling and simulation were utilized to characterize the efficacy dose response of sublingual asenapine in patients with schizophrenia and to understand the outcomes of six placebo-controlled trials in which placebo responses and dropout rates varied. The time course of total PANSS scores was characterized for placebo and asenapine treatments in a PK-PD model in which the asenapine effect was described by an Emax model, increasing linearly over the 6-week study period. A logistic regression model described the time course of dropouts, with previous PANSS value being the most important predictor. The last observation carried forward time courses were well described in simulations from the combined PANSS+dropout model. The observed trial outcomes were successfully predicted for all the placebo arms and the majority of the treatment arms. Although simulations indicated that the post hoc probability of success of the performed trials was low to moderate, these analyses demonstrated that 5 and 10 mg twice-daily (bid) doses of asenapine have similar efficacy.[50]

7 Pitavastatin Pitavastatin is an oral HMG-CoA reductase

inhibitor recently approved by the Food and Drug Administration for the treatment of primary hyperlipidemia and mixed dyslipidemia. Pitavastatin 2 mg has been shown to be noninferior to atorvastatin 10 mg and simvastatin 20 mg with respect to low-density lipoprotein cholesterol (LDL-C)-lowering ability. Additionally, pitavastatin 2 mg was shown in one study to lower LDL-C significantly more than pravastatin 10 mg. As with other HMG-CoA reductase inhibitors, primary safety concerns are related to myopathies and alterations in liver enzyme levels. While efficacy regarding beneficial effects on lipid parameters is comparable to that of other agents, a potential advantage of pitavastatin is its cytochrome P450 independent elimination, thereby reducing the likelihood of clinically significant drug-drug interactions. However, this is not a unique property, as pravastatin and rosuvastatin also possess this


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property. In light of the lack of outcome data, pitavastatin offers no clear advantage over other drugs in this class.[51]

The PK of pitavastatin was studied in Chinese healthy volunteers. Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild-type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by LC-MS. The PK parameters of pitavastatin were significantly different between the two genotyped groups. The Cmax was higher in the 388GA+ 388GG group than that in the 388AA group (39.22±8.45 vs. 22.90±4.03 ng·mL-1). The AUC0-48 and AUC0-infinity of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100.42±21.19 vs. 182.19±86.46 ng h·mL-1; 108.12±24.94 vs. 199.64±98.70 ng h·mL-1) respectively. The Cl/F was lower in the 388GA+388GG group than that in the 388AA group (12.46±4.79 vs. 19.21±3.74·h-1). The elimination of t1/2 and Tmax values showed no difference between these groups. The study showed that OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.[52]

Eleven healthy volunteers were enrolled and evaluated for the effects of statins on the pharmacokinetics of midazolam in an open-label, randomized, 3-way crossover trial with simvastatin 10 mg, atorvastatin 10 mg, and pitavastatin 2 mg. The statins had no effects on the pharmacokinetics of idazolam and its metabolite, 1'-hydroxy- midazolam. Furthermore, the area under the concentration-time curve ratios for 1'-hydroxy- midazolam/midazolam from 0 to 10 hours showed no significant differences among 3 statins (simvastatin: 0.32±0.09, atorvastatin: 0.31±0.09, and pitavastatin: 0.31±0.12). These data suggest that statins, at least at low doses used in the present study, do not affect CYP3A4 and can be used safely without influencing CAP3A4 enzyme activity.[53] The plasma concentration of pitavastatin is increased in patients with liver cirrhosis. In such patients, caution is required, although dose

reduction may not be necessary in Child-Pugh A.cirrhosis.[54] The bioavailability of the statins differs greatly, from 5% for lovastatin and simvastatin to 60% or greater for cerivastatin and pitavastatin. Clinical studies have demonstrated rosuvastatin to be the most effective for reducing low-density lipoprotein cholesterol, followed by atorvastatin, simvastatin and pravastatin. As a class, statins are generally well tolerated and serious adverse events, including muscle toxicity leading to rhabdomyolysis, are rare. Consideration of the differences between the statins helps to provide a rational basis for their use in clinical practice.[55]

8 Saxagliptin Saxagliptin is a potent and selective reversible

inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. Clinical trials have demonstrated a dose-dependent inhibition of DPP-IV by saxagliptin without serious side effects. Results have demonstrated that treatment with saxagliptin lowers blood glucose levels, with good tolerability and safety. The specific advantages of saxagliptin over other DPP-IV inhibitors may lie in its long-lived, effective and highly specific inhibition of DPP-IV, making once-daily treatment feasible, effective and safe.

Saxagliptin is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing. Saxagliptin is metabolized in vivo to form an active metabolite, and both parent drug and metabolite are excreted primarily via the kidneys. Saxagliptin reduces the degradation of the incretin hormone glucagon-like peptide-1, thereby enhancing its actions, and is associated with improved beta-cell function and suppression of glucagon secretion. Clinical trials of up to 24 weeks duration have shown that saxagliptin improves glycemic control in monotherapy and provides additional efficacy when used in combination with other oral antidiabetic agents (metformin, sulfonylurea, thiazolidinedione). Both fasting and postprandial glucose concentrations are reduce leading to clinically meaningful reductions in glycated hemoglobin, and due to the glucose-dependency of its mechanism of action, there is a low risk of hypoglycemia. Saxagliptin is


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reported to be well tolerated with a side-effect profile similar to placebo. It has a neutral effect on body weight and dose adjustment because of age, gender, or hepatic impairment is not necessary.[56,57]

The PK of saxagliptin was evaluated in rats, dogs, and monkeys and used to predict its human PK. Saxagliptin was rapidly absorbed and had good bioavailability (50-75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml·min-1·kg-1) than in dogs (9.3 ml·min-1·kg-1) and monkeys (14.5 ml·min-1·kg-1) and was predicted to be low to moderate in humans. The plasma elimination t1/2 was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The Vd values observed in rats, dogs, and monkeys (1.3-5.2 L·kg-1) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (<30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged PD properties relative to its plasma PK profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.[58]

9 Prasugrel Prasugrel is a potent, selective and irreversible

inhibitor of adenosine diphosphate (ADP)- mediated platelet aggregation that is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) comprising unstable angina pectoris/non-ST- segment- elevation myocardial infarction (unstable angina/NSTEMI) and ST-segment-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). Oral prasugrel provides rapid, potent inhibition of platelet aggregation and is an effective antiplatelet

agent for the management of patients with ACS who are undergoing PCI. In these patients, prasugrel was associated with a significantly lower incidence of ischaemic events than clopidogrel, and was particularly effective in specific subgroups of patients, such as those with diabetes mellitus. However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged > or =75 years, those weighing <60 kg and those with a history of stroke or transient ischaemic attack at the greatest risk. A lower dose of prasugrel in patients aged > or =75 years and those weighing <60 kg may help to minimize the bleeding risk, although more data are needed to establish this; prasugrel is contraindicated in patients with a history of stroke or transient ischaemic attack. Thus, prasugrel provides a new option for the management of patients with ACS who are undergoing PCI; the risk-benefit ratio should be carefully assessed before intensive antiplatelet therapy with prasugrel is initiated.[59]

Prasugrel Ticlopidine, and clopidogrel are thienopyridine prodrugs that inhibit ADP-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The three compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, varying efficiencies in the formation of active metabolites affect observed effects on the onset of action and extent of inhibition of platelet aggregation (IPA).

Knowledge of the CYP- dependent formation of ticlopidine and clopidogrel thiolactones helps explain some of the observed drug-drug interactions with these molecules and, more important, the role of CYP2C19 genetic polymorphism on the PK and PD response to clopidogrel. The lack of drug interaction potential and the absence of CYP2C19 genetic effect result in a predictable response to


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thienopyridine antiplatelet therapy with prasugrel.[60]

Although the approved loading dose is 60 mg, earlier studies of prasugrel suggested that active-metabolite exposure and PD response may be higher in Asian subjects than in white subjects. An open-label, single-dose study compared the PD response to a single 30-mg dose of prasugrel in healthy Chinese and white subjects and the response to a single 30-mg dose of prasugrel and a single 300-mg dose of clopidogrel in healthy Chinese subjects. The PK and tolerability of both drugs were also assessed. Chinese subjects were randomly allocated to receive prasugrel 30 mg or clopidogrel 300 mg; after a 14-day washout period, they received the alternative drug. White subjects received only prasugrel 30 mg. In this study, platelet inhibition was significantly higher in Chinese than in white subjects up to 2 hours after a single 30-mg dose of prasugrel. Platelet inhibition was significantly higher in Chinese subjects at all time points after a 30-mg dose of prasugrel than after a 300-mg dose of clopidogrel. Both treatments were generally well tolerated. Mean exposure to prasugrel's active metabolite was higher in Chinese than in white subjects.[61]

In a compared study on PK and PD of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Researchers suggested that mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10mg or 5mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition.[60]

10 Dronedarone Dronedarone is an oral Class III antiarrhythmic

agent which was recently approved by the US FDA for use in nonpermanent atrial fibrillation. Structurally similar to amiodarone, dronedarone is a benzofuran derivative but it lacks the iodine moiety attached to amiodarone. Based upon the investigational clinical trials to date, it appears that dronedarone has an established efficacy when compared to placebo along with exhibiting a minimal adverse effect profile. The adverse effect profile of amiodarone necessitates close and

extensive monitoring. Although a risk of pulmonary toxicity was identified in animals, long term studies in humans are needed to determine the significance of this adverse effect with dronedarone.[63,64] Oral dronedarone was generally well tolerated in the treatment of adult patients with AF and/or atrial flutter in clinical studies. The incidence of diarrhoea, nausea, bradycardia, rash and QT-interval prolongation was significantly higher with oral dronedarone than placebo in the large ATHENA study; however, serious cardiac-related adverse events were observed in <1% of oral dronedarone recipients.[65]

11 Besifloxacin Besifloxacin is a novel fluoroquinolone that

has never been used systemically and that possesses structural modifications intended to improve its potency compared to other fluoroquinolones. This investigation was conducted to evaluate the nonclinical pharmacokinetics, safety, and pharmacodynamics of besifloxacin. Proksch et al evaluated the ocular penetration and systemic exposure to besifloxacin, a fluoroquinolone antibiotic, following topical ocular administration to animals and humans. Besifloxacin ophthalmic suspension (0.6%) was administered as a topical ocular instillation to pigmented rabbits, cynomolgus monkeys, and human subjects. At predetermined intervals after dosing, samples of ocular tissues and plasma were collected and analyzed for besifloxacin levels using LC/MS/MS methods. Besifloxacin demonstrated good ocular penetration in rabbits and monkeys, with rapid absorption and sustained concentrations observed in anterior ocular tissues through 24 h after a single administration. Maximum besifloxacin concentrations in conjunctiva, cornea, and aqueous humor of monkeys were 6.43 µg·g-1, 2.10 µg·g-1, and 0.796 µg·mL-1, respectively, after a single topical dose, and concentrations declined in these tissues with an apparent t1/2 of 5-14 h. Following a single topical ocular administration to humans, the maximum besifloxacin concentration in tears was 610 µg·g-1 with concentrations decreasing to approximately 1.6 µg·g-1 at 24 h. The resulting pharmacokinetic parameters for besifloxacin in human tears were evaluated relative to the MIC90 values (µg·mL-1) for


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besifloxacin against Streptococcus pneumoniae (0.125), S. aureus (0.25), S.epidermidis (0.5), and Haemophilus influenzae (0.06). Following a single topical administration, the Cmax/MIC90 ratios for besifloxacin in human tears were > or =1,220, and the AUC0-24/MIC90 ratios were > or =2,500 for these relevant ocular pathogens. Following repeated 3-times daily (TID) topical ocular administration to human subjects with clinically diagnosed bacterial conjunctivitis, maximum besifloxacin concentrations in plasma were less than 0.5 ng·mL-1 on average. The results of the current investigation provide a PK/PD-based rationale that supports the use of besifloxacin for the safe and effective treatment of ocular infections.[66] A LC/MS/MS method was used to measure besifloxacin concentrations in tear samples collected after topical ocular administration to humans; besifloxacin concentrations were 610±540 µg·g-1 at 15 min and 1.60±2.28 µg·g-1 at 24h.[67]

Besifloxacin displayed activity in in vitro antimicrobial efficacy studies and also demonstrated efficacy in an in vivo murine infection model. Besifloxacin demonstrated excellent ocular PK in rabbits, with ocular mean residence times >7 h, and conjunctival concentrations in excess of the MIC90 for nonresistant ophthalmic isolates for >12 h following a single dose. PK modeling from these data indicated that besifloxacin has the potential to demonstrate efficacy against ophthalmologic pathogens with a TID dosing regimen. It is also demonstrated reasonably low plasma protein binding in rat and human models, as well as good metabolic stability across species. Besifloxacin in rabbits and dogs, the compound showed excellent topical ocular tolerance, as well as a favorable genotoxicity and phototoxicity profile. Besifloxacin exhibits an encouraging nonclinical PD, PK, and safety profile that supports clinical development as a topical agent for the potential treatment of ophthalmic infections.[68]

12 Tolvaptan Tolvaptan is an orally administered,

nonpeptide, selective arginine vasopressin V2 receptor antagonist that increases free water clearance, thereby correcting low serum sodium levels. SALT-1 and -2, two identical, randomized,

double-blind, placebo-controlled, multicentre trials, included patients with hypervolaemic or euvolaemic hyponatraemia associated with heart failure, cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion. This beneficial effect of tolvaptan on serum sodium levels in SALT-1 and -2 was observed in patients with mild and in those with marked hyponatraemia at baseline. Tolvaptan was generally well tolerated in clinical trials. The most frequently reported adverse events were thirst and dry mouth, which result from the pharmacodynamic effects of the drug.[69,70]

Two single-center, double-blind, randomized, placebo-controlled, sequentially enrolled studies were conducted. In study 1, 8 subjects (6 active/2 placebo) received 60, 90, 120, 180, or 240 mg tolvaptan/matching placebo. In study 2, 9 subjects (6 active/3 placebo) received 180, 240, 300, 360, 420, or 480 mg tolvaptan/matching placebo. Increases in tolvaptan Cmax were less than dose-proportional and plateaued at doses greater than 240 mg; AUCinfinity increased proportionally with dose. Changes in serum K+, creatinine clearance, and Na+, K+, and osmolality urinary excretion were similar to the placebo group for the 0- to 24-hour interval following dosing. Changes were observed in plasma arginine vasopressin, serum aldosterone, and plasma renin activity but were not clinically significant. Increases were seen in mean serum Na+ concentrations (4-6 mEq·L-1), plasma osmolality (approximately 8 mOsm·kg-1), and free water clearance (approximately 6 mL·min-1) throughout 0 to 24 hours; none of these increases was dose dependent. Only total urine volume excretion (0-72 h postdose) increased linearly with dose. As plasma tolvaptan concentrations increased, the duration that the urine excretion rate remained above baseline rates also increased. The most frequent adverse events--excess thirst, frequent urination, and dry mouth--appeared to be related to the pharmacological action of tolvaptan. No dose- limiting toxicities were observed.[71]

A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of tolvaptan + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of


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hydrochlorothiazide (HCTZ), and 30 mg pf tolvaptan + 100 mg of HCTZ. Doses were separated by a 48-hour washout. Blood and urine samples were collected at scheduled timepoints during the 24 hours after administration of study drug for the determination of PK and PD parameters. No clinically significant changes were noted in the pharmacokinetic profiles of tolvaptan and furosemide or tolvaptan and HCTZ when coadministered. Free water clearance, 24-hour urine volume, plasma sodium and argentine vasopressin concentrations, and plasma osmolality were higher, and urine osmolality was lower when tolvaptan was administered either alone or in combination with furosemide or HCTZ, compared with furosemide or HCTZ administered alone. At 24 hours postdose, plasma renin activity was increased after furosemide or HCTZ administered alone or with tolvaptan, but it was unchanged after tolvaptan alone. Tolvaptan did not significantly affect the natriuretic activity of furosemide or HCTZ. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan.[72]

13 Iloperidone Iloperidone, 1- [4(-)[3(-)[4-(6-fluro-1,2-benz

isoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, is a new-generation atypical antipsychotic agent, acting as a serotonin/dopamine (5-HT2A/D2) antagonist for the treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Chemically, iloperidone is a benzisoxazole, like risperidone, and shows a multiple receptor binding profile, sharing this feature with the other atypical antipsychotic agents. Administered orally, the drug is highly bound to plasma proteins and extensively metabolised. Several clinical trials have been carried out, to check efficacy, safety and side effects. Iloperidone pharmacokinetics and pharmacodynamics are presented herein, together with an evaluation of clinical safety and efficacy results.[73]

Most of antipsychotics drugs undergo extensive first-pass metabolism and are cleared almost exclusively by metabolism, except for amisulpride whose clearance is largely due to urinary excretion. Risperidone has metabolic routes in common with ziprasidone but shows differences

in regard to other main pathways: the iloperidone moiety of risperidone is oxidised by CYP2D6 to the active 9-hydroxyrisperidone, whereas the benz- isothiazole of ziprasidone is primarily oxidised by CYP3A4, yielding sulfoxide and sulfone derivatives with low affinity for target receptors in vitro. Olanzapine, quetiapine and zotepine also have some common metabolic features. However, for the thienobenzodiazepine olanzapine a main metabolic route is direct conjugation at the benzodiazepine nucleus, whereas for the dibenzothiazepine quetiapine and the dibenzo- thiepine zotepine it is CYP3A4-mediated oxidation, leading to sulfoxidation, hydroxylation and dealkylation for quetiapine, but N-demethylation to the active nor-derivative for zotepine. Although the promising iloperidone and perospirone antipsychotics share some metabolic routes with the structurally related available drugs, they too have pharmacologically relevant compound- specific pathways. For some of the new antipsychotics we know the isoenzymes involved in their main metabolic pathways and the endogenous and exogenous factors that, by affecting enzyme activity, can potentially modify steady-state concentrations of the parent drug or its metabolites, but we know very little about others, such as amisulpride isomers, nemonapride. For yet others, information is scarce about the activity of the main metabolites and whether and how these contribute to the effect of the parent drug. Aging reduces the clearance of most antipsychotics, except amisulpride and ziprasidone. Liver impairment has little or no effect on the pharmacokinetics of olanzapine, quetiapine, risperidone (and 9-hydroxy-risperidone) and ziprasidone, but information is lacking for amisulpride. Renal impairment significantly reduces the clearance and prolongs the elimination t1/2 of amisulpride and risperidone. Again, studies are still not available for some drugs (zotepine) and have focused on the parent drug for others (olanzapine, quetiapine, ziprasidone) despite the fact that renal impairment would be expected to lower the clearance of more polar metabolites.[74] Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3- or 5-mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5


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mg (from 2.2 to 5.2 ng·mL-1/ for Cmax, and 16 to 50 ng·mL -1·h-1 for AUC). Iloperidone was eliminated slowly with a mean t1/2 of 13.5 to 14.0 h. Coadministration with food did not significantly affect AUC, Tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadmini- stration of food reduced the incidence and severity of these events.[74-76] Identification of some of the unknown metabolites in rat bile was achieved successfully by combination of LC/NMR and LC/MS with a minimum amount of sample cleanup. The utility of coupling a semipreparative HPLC to LC/MS instrument for further characterization of collected metabolites was demonstrated. It was shown that iloperidone was metabolized by O-dealkylation processes to yield 6-fluoro-3 (-)[1-(3-hydroxy- propyl)-4-piperidinyl] -1, 2-benzisoxazole and 1(-)[4(-)[3(-)[4-(6-fluoro- 1,2- benzisoxazol-3-yl) -1-piperidinyl]propoxy]-2- hydr-oxylphenyl] ethanone. Oxidative N-dealkylation led to the formation of 6-fluoro-3-(4- piperidinyl)- 1,2-benz isoxazole and a secondary metabolite, 3(-)[(4- acetyl-2- methoxy)phenoxy] propionic acid. Ilope- ridone was reduced to produce 4(-)[3(-) [4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl] -prop-oxy] -3-methoxy-α-methyl benzene methanol as the major metabolite in humans and rats. Hydroxylation of iloperidone produced 1(-)[4(-) [3(-)[4-(6- fluoro-1,2-benziso-xazol- 3-yl)- 1-piperidinyl] propoxy]-2-hydroxy-5-methoxyphenyl] ethanone and 1(-)[4(-)[3(-)[4- (6-fluoro- 1,2-benzisoxazol- 3-yl)-1-piperidinyl]-3- methoxyphenyl] propoxy] -2- hydroxyethanone, the later of which was found to be the principal metabolite in dogs.[77]

14 Coartem Coartem is a complex preparation of

artemether and lumefantrine. It is used for the Treatment of infections due to Plasmodium falciparum or mixed infections including P. falciparum. Artemether and lumefantrine (AL), the active constituents of Coartem exhibit complementary PK profiles.

The efficacy and safety of artemether- lumefantrine for the treatment of malaria in

nonimmune populations are not well defined. In this study, 165 nonimmune patients from Europe and non-malarious areas of Colombia with acute, uncomplicated falciparum malaria or mixed infection including P. falciparum were treated with the six-dose regimen of artemether-lumefantrine. The parasitologic cure rate at 28 days was 96.0% for the per protocol population (119/124 patients). Median times to parasite clearance and fever clearance were 41.5 and 36.8 hours, respectively. No patient had gametocytes after Day 7. Treatment was well tolerated; most adverse events were mild to moderate and seemed to be related to malaria. There were few serious adverse events, none of which were considered to be drug-related. No significant effects on ECG or laboratory parameters were observed. In conclusion, the six-dose regimen of artemether-lumefantrine was effective and well tolerated in the treatment of acute uncomplicated falciparum malaria in nonimmune patients.[78]

Coartem efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat.[79]

The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. It offers the advantage of rapid clearance of parasites by artemether and the slower elimination of residual parasites by lumefantrine. The combination can be used in all populations except pregnant mothers in the first trimester where safety is still uncertain.[80]

Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination t1/2 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether(A) and lumefantrine(L), an effect which is more apparent for the highly lipophilic


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lumefantrine. The pharmacokinetics of A or L is similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of AL is increasing within a range of settings, including infants and children.[81] A dose-response relationship was demonstrated between the volume of soya milk administered and lumefantrine bioavailability. AL administration with soya milk increased the lumefantrine AUC more than five fold. The estimated mean volume of soya milk required to obtain 90% of maximum effect (in terms of lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat). It is showed that coadministration of A-L with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of lumefantrine in healthy adult volunteers.[82] Coartem is a well-tolerated, fast-acting and effective blood schizontocidal drug that serves primarily in the treatment of uncomplicated falciparum malaria that is resistant to other antimalarials. Initial clinical parasitological response relies mainly on the artemether component, while lumefantrine affect radical cure. The absorption of lumefantrine is poor during the fasting state, the normal condition in acutely ill malaria patients, but with return to normal diet it becomes adequate. This highlights the need for an appropriate adjustment of the dose regimen. In the area where Plasmodium falciparum shows the highest degree of multidrug resistance worldwide, the best results (99% cure) were obtained with a

six-dose regimen given over 5 days. Extensive cardiological investigations have demonstrated the high cardiac safety of coartemether.[83]

15 Pazopanib Pazopanib (GW786034) is a second-

generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. Preclinical evaluation has revealed excellent antiangiogenic and antitumor activity, and synergism was observed in combination with chemotherapeutic drugs. Significant antitumor activity was found in animal models of a variety of tumors, accompanied by desirable pharmacokinetics and oral bioavailability.

In Hurwitz et al’s study on the safety, PK, and clinical activity of pazopanib, hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of > or =800 mg once daily. The mean elimination half-life at this dose was 31.1 h. A mean target trough concentration (C(24), 15 µg mL -1 (34 µmol·L -1) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of > or = 6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of > or =800 mg once daily or 300 mg twice daily. They conclude that pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.[84] Takahashi et al investigated the treatment of

choroidal neovascularization (CNV) by pazopanib hydrochloride, a multitargeted kinase inhibitor, in mice induced by rupture of Bruch membrane with laser photocoagulation. Mice were treated with pazopanib by gavage or periocular injection, and the area of CNV was measured. Twice-daily gavage of pazopanib, 100 mg·kg-1, suppressed the development of CNV by 93%. Treatment of


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established CNV between days 7 and 14 with 8, 40, or 200 mg/kg per day reduced CNV by 0%, 58%, and 71%, respectively. Substantial regression (40%) of CNV was also achieved after periocular injection of pazopanib. A single oral dose of 4 or 100 mg·kg-1 resulted in an area under the curve from time 0 to the last quantifiable concentration of 129.6 and 752.0 µg·h·mL -1, respectively. After 7 days of 4, 20, or 100 mg/kg twice a day by gavage, plasma levels were 1300, 4900, and 5800 ng·mL -1 and levels in the retina/choroid were 4800, 28 800, and 38 000 ng·g -1 of tissue. Orally administered pazopanib has good bioavailability to the retina/choroid and strongly suppresses CNV in mice. Treatment with pazopanib after CNV is established causes dose-dependent regression of CNV. Researchers conclude that Pazopanib may be useful for treatment of CNV in humans.[85]

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. Researchers have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF- induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in Cmax and Ctrough, Kumar et al investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus oral dosing and continuous infusion), It was showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphory- lation in mouse lungs. Furthermore, the steady state

concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.[86] Phase I clinical trials have revealed manageable toxicities and desirable pharmacokinetics as well as activity in renal cancer and several other tumors. Ongoing trials are further evaluating pazopanib in a variety of malignancies. [87]

16 Benzyl alcohol Benzyl alcohol is indicated for pts infected

with Pediculus humanus capitas (Head lice) of the scalp hair. No study reported on PK of benzyl alcohol in animals and patients.

17 Everolimus Everolimus is a mTOR inhibitor and is used for

the treatment of advanced renal cell carcinoma. Comparative PK analysis of everolimus was carried out in rats and mice. Blood cell partitioning, plasma protein binding and PK parameters of everolimus in blood and tissues of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity. The PK properties of everolimus differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t1/2, oral bioavailability, Vd, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a 2-fold increase in tumor levels of everolimus at steady state, whereas in rats, a 7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of everolimus were four- to eight-fold greater in rats than in mice. Rat tumors had a >2-fold greater plasma content and permeability compared to mouse tumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04-0.35) were observed in both species after daily administration with


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similar Cmax and AUC values of unbound (free) everolimus. These free levels of everolimus are exceeded in serum from cancer patients receiving clinically beneficial daily regimens. In rodents, brain penetration of everolimus was poor, but was dose-dependent and showed over-proportional uptake in rats with a longer t1/2 compared to the systemic circulation. The study results showed that PK of everolimus differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of everolimus may be more appropriate for treatment of brain tumors.[88]

After receiving single oral doses of 100 mg sotrastaurin, 2 mg everolimus, and the drug combination, coadministration of everolimus decreased sotrastaurin Cmax from 638±295 to 539±211 ng·mL-1 yielding a combination/ monotherapy ratio of 0.87. Sotrastaurin total AUC was not altered by everolimus with values of 3660 ±1853 versus 3630 ±2006 ng·h·mL-1 and a ratio of 1.00. Sotrastaurin increased everolimus Cmax from 15 ±6 to 16±6 ng·mL-1 yielding a ratio of 1.15 and increased everolimus total AUC from 114±50 to 137 ±56 ng·h·mL-1 yielding a ratio of 1.20. The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels can not be excluded. Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin PK to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.[89]

The PK of everolimus in Japanese patients was similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with everolimus at 10 mg·d-1 showed marked tumor responses. Okamoto et al’s study on the treatment of Japanese cancer patients with everolimus may be undertaken with the expectation that previously determined PK and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer.[90]

18 Febuxostat

Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The prevalence of gout has been increasing in epidemic proportions over the last several decades. Hyperuricemia has been shown to be associated with metabolic syndrome and to be an independent risk factor for cardiovascular disease. Associations between hyperuricemia, obesity and aging have provided an impetus in recent years to develop alternative methods of treating hyperuricemia and gout. Febuxostat has been shown to quickly and effectively lower serum urate levels in patients with chronic gout.

The study will determine whether the drug can be administered regardless of food or antacid. It will therefore influence how the drug should be administered. To evaluate the effects of food or antacid on the PK and/or PD of febuxostat, four Phase I, two-period, crossover studies were performed in healthy subjects. Subjects either received single 40-mg (n = 24), multiple 80 mg (n = 24) and single 120-mg (n = 20) doses of febuxostat in fasting and nonfasting onditions, or received single 80-mg (n = 24) doses alone or with antacid. ood caused a decrease in Cmax (38-49%) and AUC (16-19%) of febuxostat t different dose levels following single or multiple oral dosing with febuxostat. However, a slightly greater percent decrease in serum uric acid concentrations (58% vs. 51%) after multiple dosing with 80 mg of febuxostat under nonfasting conditions was observed, which was statistically but not clinically significant. Antacid caused a decrease in Cmax (32%), but had no effect on AUC of febuxostat. Febuxostat was safe and well tolerated in all studies. Even though food caused a decrease in the rate and extent of absorption of febuxostat, this decrease was not associated with a clinically significant change in febuxostat pharmacodynamic effect. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption. Therefore, febuxostat can be administered regardless of food or antacid intake.[91] The PK and PD, efficacy and adverse events and use in patients with comorbid conditions. In the phase III trials leading up to the drug's approval by both the


116

European Commission in 2008 and the U.S. FDA in 2009.[92] The effect of age and gender on the PK, PD, and safety of once-daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary PK or PD parameters between subjects aged 18 to 40 years and >or =65 years. Although Cmax and AUC24, for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng·mL-1, and 62.8 vs 53.9 ng·h·mL-1, for Cmax and AUC24, respectively), the differences were not considered clinically significant and could be largely accounted for by weight differences between male and female subjects. For PD parameters, even though the decrease percentage in serum uric acid 24-h mean concentration was slightly greater in women than in men (59% vs 52%), this difference was not considered clinically meaningful. Febuxostat was well tolerated in male and female subjects in both age groups. Age or gender had no clinically significant effect on the PK, PD, or safety of febuxostat. Therefore, febuxostat does not require any dose adjustments based on age or gender.[93] To investigate the PK, PD andsafety of febuxostat over a range of oral doses in healthy subjects. In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3-14. During the course of the study, blood and urine samples were collected to assess the PK of febuxostat and its metabolites, and its PD effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study. Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5-1.3 h. The PK of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10-120 mg dose range, with a mean apparent total clearance of 10-12 L·h-1 and an apparent volume of distribution at steady state of 33-64 L. The harmonic mean elimination t1/2 of febuxostat ranged from 1.3 to 15.8

h. The increase in the AUC of febuxostat at doses >120 mg appeared to be greater than dose proportional, while the febuxostat Cmax was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22-44% of the dose) and oxidation (2-8%) with only 1-6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% for all doses and was dose linear for the 10-120 mg·d-1 dosage range. The majority of adverse events were mild-to-moderate in intensity. Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear PK and dose-response relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.[94]

Mukoyoshi et al’s study on in vitro drug-drug interaction studies with febuxostat obtained following results: (1) The potential for drug-drug interactions with febuxostat was examined in the following three in vitro systems: the characteristics of the binding of febuxostat to human plasma proteins; identification of the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes participating in the metabolism of febuxostat; and the potential inhibitory effects of febuxostat on typical CYP reactions; (2) The results have shown that the presence of ibuprofen or warfarin did not change the plasma protein binding of febuxostat, and that febuxostat did not influence the plasma protein binding of ibuprofen or warfarin. These results indicate that there is little possibility that febuxostat causes a drug-drug interaction by binding to albumin; (3) The UGT 1 and 2 families were involved in the glucuronidation, and several CYPs participated in the metabolism of febuxostat, suggesting that there is little possibility that the blood concentration of febuxostat varies widely even if febuxostat is concomitantly administered with drugs that inhibit CYP or UGT enzyme. Examination of the inhibitory effect of febuxostat


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on CYP enzymes suggests that febuxostat minimally inhibits the activities of any CYP; and (4) The results demonstrate that febuxostat is a novel anti-hyperuricaemia drug with low drug-drug interaction potential in clinical use.[95]

19 Milnacipran Milnacipran is a serotonin and norepinephrine

reuptake inhibitor with negligible effects on any presynaptic or postsynaptic receptors. The antidepressant efficacy of milnacipran has been clearly established in a number of randomized, double-blind, placebo-controlled clinical trials, and it has been widely used for treating major depressive disorder. Moreover, evidence suggests that milnacipran is effective and tolerable in the treatment of fibromyalgia and may have usefulness for fatigue and anxiety symptoms. The phase III trials have employed comprehensive composite endpoints to more accurately capture the many complex domains. Milnacipran's efficacy was not limited to the shortterm, 12-week trials. It also demonstrated durability of response for up to 1 year. Its safety and tolerability were typical of its class, and it was generally well tolerated.[96] Milnacipran has unique PK and PD characteristics that distinguish it from the other marketed serotonin and norepinephrine reuptake inhibitors, venlafaxine, desvenlafaxine, and duloxetine such as equipotent serotonin and norepinephrine reuptake inhibition and a linear dose-concentration trend at therapeutic doses. The t1/2 of milnacipran is approximately 8 h.[97] Metabolism of milnacipran was limited: approximately 50% unchanged drug, 30% as glucuronide and 20% as oxidative metabolite (mainly F2800 the N-dealkyl metabolite). Milnacipran administration to PM2D6 and PM2C19 subjects did not increase parent drug exposure or decrease metabolite exposure. Milnacipran oxidative metabolism is not mediated through CYP2D6 or CYP2C19 polymorphic pathways nor does it significantly interact with CYP1A2, CYP2C19, CYP2D6 or CYP3A4 activities. Limited reciprocal PK interaction between milnacipran and CYP isoenzymes would confer flexibility in the therapeutic use of the drug when combined with antidepressants. Drug-drug interaction risk would be low, even if the combined treatments were likely

to inhibit CYP2D6 and CYP2C19 isoenzyme activities.[98] Milnacipran does not inhibit the cytochrome P 450 system, indicating minimal propensity for drug-drug interactions.[97] Potential drug-drug interactions were evaluated by comparing milnacipran PK parameters between periods 1 and 3. A steady-state of fluoxetine and its metabolite was effectively reached by the end of the 3-week period. A steady-state of milnacipran was reached on day 2 of both periods 1 and 3. Trough concentrations of milnacipran were 66 and 65 ng·mL-1 before and after the fluoxetine administration period, respectively. Cmax values were 226 and 248 ng·mL-1. When comparing the kinetic parameters of milnacipran before and after fluoxetine treatment, all the 90% confidence intervals were in the 20% range. No significant difference in the adverse events of milnacipran was observed before or after fluoxetine administration.[99]

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