The Journal of Clinical Pharmacology recent issues

The Effect of Age and Gender on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase

Khosravan, R., Kukulka, M. J., Wu, J.-T., Joseph-Ridge, N., Vernillet, L. — 2008-08-26

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 effect of age and gender on the pharmacokinetics, pharmacodynamics, 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 pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and ≥65 years. Although unbound peak concentration (C_max,u) and area under the concentration-time curve (AUC_24,u) for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P ≤ .01, and 62.8 vs 53.9 ngxh/mL, P ≤ .05, for C_max,u and AUC_24,u, respectively), the differences were not considered clinically significant and could be largely accounted for by weight differences between male and female subjects. For pharmacodynamic parameters, even though the percentage decrease in serum uric acid 24-hour mean concentration was slightly greater in women than in men (59% vs 52%, P ≤ .01), 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 pharmacokinetics, pharmacodynamics, or safety of febuxostat. Therefore, febuxostat does not require any dose adjustments based on age or gender.

Pharmacokinetics and Pharmacodynamics of Pegfilgrastim in Subjects With Various Degrees of Renal Function

Yang, B.-B., Kido, A., Salfi, M., Swan, S., Sullivan, J. T. — 2008-08-26

A phase I study was conducted to evaluate the effects of renal function on the pharmacokinetics and pharmacodynamics (absolute neutrophil count [ANC]) of pegfilgrastim in nonneutropenic subjects. Thirty subjects categorized into 5 renal function groups (normal, mildly impaired, moderately impaired, severely impaired, and end-stage renal disease) received 1 subcutaneous injection of pegfilgrastim at 6 mg. The ANC profiles after pegfilgrastim administration were similar across different renal function groups. No discernable correlation between pharmacokinetic parameter values and degree of renal impairment was observed; the mean values ranged from 147 to 201 ng/mL for C_max and from 7469 to 8513 ngxh/mL for AUC. Results suggest that the kidney has no important role in the elimination of pegfilgrastim. Therefore, no dosage adjustment for renal impairment is indicated for pegfilgrastim.

Pharmacokinetics of Efavirenz When Co-administered With Rifampin in TB/HIV Co-infected Patients: Pharmacogenetic Effect of CYP2B6 Variation

2008-08-26

The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady-state pharmacokinetics of efavirenz (600 mg/d) in TB/HIV co-infected patients receiving concomitant rifampin, a potent CYP inducer. In the 26 patients studied, CYP2B6 c.516GG, GT, and TT genotype frequencies were 0.27, 0.50, and 0.23, respectively. Mean plasma efavirenz area under the curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs 27.6 µgxh/mL, P < .0001) or GG genotype (107 vs 23.0 µgxh/mL, P < .0001). Apparent oral clearance (CL/F) was significantly lower in patients with CYP2B6 c.516TT than in those with GT genotype (2.1 vs 8.4 mL/min/kg, P < 0.0001) and GG genotype (2.1 vs 9.9 mL/min/kg, P < .0001). No differences in efavirenz exposure or CL/F existed between patients with CYP2B6 c.516GT and GG genotypes. Our results indicate that CYP2B6 c.516TT genotype can be used to identify efavirenz poor metabolizers in patients co-treated with rifampin.

Evaluation of a [13C]-Dextromethorphan Breath Test to Assess CYP2D6 Phenotype

Leeder, J. S., Pearce, R. E., Gaedigk, A., Modak, A., Rosen, D. I. — 2008-08-26

A [¹³C]-dextromethorphan ([¹³C]-DM) breath test was evaluated to assess its feasibility as a rapid, phenotyping assay for CYP2D6 activity. [¹³C]-DM (0.5 mg/kg) was administered orally with water or potassium bicarbonate-sodium bicarbonate to 30 adult Caucasian volunteers (n = 1 each): CYP2D6 poor metabolizers (2 null alleles; PM-0) and extensive metabolizers with 1 (EM-1) or 2 functional alleles (EM-2). CYP2D6 phenotype was determined by ¹³CO₂ enrichment measured by infrared spectrometry (delta-over-baseline [DOB] value) in expired breath samples collected before and up to 240 minutes after [¹³C]-DM ingestion and by 4-hour urinary metabolite ratio. The PM-0 group was readily distinguishable from either EM group by both the breath test and urinary metabolite ratio. Using a single point determination of phenotype at 40 minutes and defining PMs as subjects with a DOB ≤0.5, the sensitivity of the method was 100%; specificity was 95% with 95% accuracy and resulted in the misclassification of 1 EM-1 individual as a PM. Modification of the initial protocol (timing of potassium bicarbonate-sodium bicarbonate administration relative to dose) yielded comparable results, but there was a tendency toward increased DOB values. Although further development is required, these studies suggest that the [¹³C]-DM breath test offers promise as a rapid, minimally invasive phenotyping assay for CYP2D6 activity.

Glutathione S-Transferase A1 Genetic Variants Reduce Busulfan Clearance in Children Undergoing Hematopoietic Cell Transplantation

2008-08-26

The effect of glutathione S-transferase variants on pediatric busulfan metabolism was investigated by noncompartmental and population pharmacokinetic modeling. Twenty-nine children who underwent related or unrelated bone marrow or umbilical cord blood hematopoietic cell transplant were retrospectively studied. GSTA1, GSTP1, and GSTM1 variants were explored for their effects on busulfan exposures. Noncompartmental pharmacokinetic analyses showed that carriers of GSTA1*B had a 2.6-fold higher busulfan area under the curve and concentration at steady state compared with noncarriers (P ≤ .01). Population pharmacokinetic modeling demonstrated that carriers of GSTA1*B reduced busulfan clearance by 30%. Monte Carlo simulations were then performed to assess busulfan dosing regimens based on GSTA1 genotypes. Simulations determined that dosing based on GSTA1 genotype, weight, and age resulted in fewer children exceeding the upper therapeutic limit compared with dosing using age and weight only. Larger, prospective studies are needed to confirm these findings.

Pharmacokinetic-Pharmacodynamic Modeling of Dalbavancin, a Novel Glycopeptide Antibiotic

Dowell, J. A., Goldstein, B. P., Buckwalter, M., Stogniew, M., Damle, B. — 2008-08-26

Dalbavancin is a novel glycopeptide with a 2-dose, once-weekly dosing regimen that is being developed for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Monte Carlo simulations were performed for dalbavancin using population pharmacokinetic data and minimum inhibitory concentrations (MICs) for clinical trial isolates. The time-dependent target was the maintenance of free drug concentrations above the MIC for 14 days (t > MIC). The concentration-dependent target was an area under the concentration-time curve (AUC)/MIC ratio of approximately 1000 for Staphylococcus aureus and 100 for Streptococcus sp. These targets were used to estimate susceptibility breakpoints for dalbavancin. For S aureus, the estimated susceptibility breakpoint was ≤0.5 µg/mL using AUC_{14 days}/MIC and ≤1 µg/mL using t > MIC. For Streptococcus sp, the estimated susceptibility breakpoint was at least 2 µg/mL. Because dalbavancin MIC₉₀s for these species are well below these values, the analysis supports the use of once-weekly dosing regimens of dalbavancin in the treatment of complicated skin and skin structure infections.

Evaluation of the Administration Time Effect on the Cumulative Cortisol Suppression and Cumulative Lymphocytes Suppression for Once-Daily Inhaled Corticosteroids: A Population Modeling/Simulation Approach

Wu, K., Goyal, N., Stark, J. G., Hochhaus, G. — 2008-08-26

Inhaled glucocorticoids continue to be first-line therapy in asthma. To improve improving patient compliance, newer inhaled glucocorticoids have been developed for once-a-day treatment. This study was interested in identifying the optimal time of dosing using 2 surrogate markers of glucocorticoid action. A previously published study on the pharmacokinetics and pharmacodynamics (cortisol and blood lymphocyte suppression) of the inhaled glucocorticoids budesonide and fluticasone propionate was reanalyzed using a population pharmacokinetic approach. A stochastic numerical simulation using NONMEM assessed the effects of time of dosing on cortisol (side effect parameter) and blood lymphocytes (side effect and effect parameter). The effects on cortisol were more pronounced when the glucocorticoids were given in the morning, whereas the effects on lymphocytes (an effect controlled by endogenous and exogenous glucocorticoids) were maximized when dosing occurred in the late afternoon or evening. Twice-daily dosing of the same dose resulted in smaller differences between maximum and minimal effects. These were of no clinical relevance. Simulations for once-daily dosing support clinical studies that reported a higher antiasthmatic effect and lower cortisol suppression when once-daily dosing occurs in the evening.

Practical Therapeutic Drug Management in HIV-Infected Patients: Use of Population Pharmacokinetic Models Supplemented by Individualized Bayesian Dose Optimization

Neely, M., Jelliffe, R. — 2008-08-26

Individualized, model-based, target-oriented optimal concentration-controlled dosing of HIV medications can be beneficial to patients for whom there are limited dosing guidelines, such as children, adolescents, or patients with altered physiologic function. Barriers to this approach include lack of training, expertise, and access to appropriate software to assist the clinician. The authors present 4 illustrative clinical cases of HIV-infected patients whose therapy was optimized using population pharmacokinetic models (here generated from published studies) and supplemented by individualized Bayesian adaptive control of dosage regimens as implemented in the MM-USCPACK software. These 4 cases illustrate how clinicians can maximize therapeutic success in (1) patients with reduced drug clearance, (2) young adolescents transitioning to adult physiology, (3) patients with dose-dependent toxicity, and (4) adolescents with limited therapeutic options.

A Study of the Pharmacokinetic Interaction of Istradefylline, a Novel Therapeutic for Parkinson's Disease, and Atorvastatin

2008-08-26

The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n = 16) or placebo (n = 4) daily for 14 days. Plasma samples collected for 96 hours after atorvastatin administration, alone and in combination, were analyzed for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin. Istradefylline increased atorvastatin C_max (53%), AUC_0- (54%), and t_1/2 (27%); and increased AUC_0- for orthohydroxy atorvastatin (18%), but had no significant effect on its C_max or t_1/2; and had minimal effect on parahydroxy atorvastatin AUC_0-. The lack of inhibition by istradefylline on metabolite systemic exposure, combined with increased atorvastatin systemic exposure, suggests a predominant P-glycoprotein inhibitory effect of istradefylline.

Abstracts: Thirty-Seventh Annual Meeting American College of Clinical Pharmacology September 14-16, 2008 Philadelphia, Pennsylvania

2008-08-26

Quantitative Clinical Pharmacology: Guidance for Authors and a Call for Papers

Krishna, R. — 2008-07-23

Same Drug, Different Dosing: Differences in Dosing for Drugs Approved in the United States, Europe, and Japan

Malinowski, H. J., Westelinck, A., Sato, J., Ong, T. — 2008-07-23

With globalization of the pharmaceutical industry, newly approved drugs nearly always become available worldwide, including the 3 major pharmaceutical regions: the United States, Europe, and Japan. One might think that these drugs would have the same recommended dosing throughout the world, but this appears not to be true in many instances. The objective of this study was to identify any patterns of differences in labeled dosing. Approved labeling, for the most widely prescribed proprietary drugs in the United States, was used as a basis for this study. Dosing was compared, for common indications, for the United States, Europe, and Japan. Overall, these data indicate that there are numerous differences in approved dosing for drugs approved in all 3 regions. For about half of the drugs studied, dosing in Japan is considerably lower than the United States or Europe. Some differences in dosing are also apparent between the United States and Europe.

Pharmacokinetics of High-Dose Abetimus Sodium in Normal Subjects With Specific Assessment of Effect on Coagulation

Linnik, M. D., O'Rourke, A. M., Crowther, M. A. — 2008-07-23

Abetimus sodium is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-double-stranded DNA antibody levels. The safety and pharmacokinetics of abetimus were evaluated in 24 healthy volunteers at intravenous doses of 600 mg, 1200 mg, and 2400 mg. The mean half-life ranged from 0.8 to 1.5 hours. Maximum exposure assessed by maximum observed plasma concentration was dose proportional. Total exposure assessed by area under the plasma concentration–time curve was dose proportional between 1200-mg and 2400-mg doses and greater than proportionate between the 600-mg and 1200-mg doses. Abetimus was well tolerated in all dose groups, with adverse events observed in 33.3% (2/6) of placebo subjects and 16.7% (3/18) subjects receiving abetimus. No clinically significant effects were observed on laboratory values, vital signs, or electrocardiogram, with the exception of a transient, dose-dependent, prolongation in activated partial thromboplastin time. In vitro coagulation studies suggested that the effect on activated partial thromboplastin time was attributable to a nonspecific interaction rather than specific factor depletion. Exposure to abetimus at intravenous doses of 600 mg, 1200 mg, and 2400 mg was well tolerated. Total exposure assessed by area under the plasma concentration–time curve was greater than dose proportional across the dose range of 600 mg to 2400 mg.

Absolute Oral Bioavailability and Disposition of Deferasirox in Healthy Human Subjects

Sechaud, R., Robeva, A., Belleli, R., Balez, S. — 2008-07-23

Deferasirox is a novel iron chelator formulated as tablets for dispersion (suspension) for once-a-day oral administration. The current study evaluated the absolute bioavailability of a single 375-mg oral dose of deferasirox administered in the form of tablets compared with a 130-mg intravenous infusion of deferasirox. Since this was a first-in-man study using the deferasirox intravenous (IV) formulation, the safety and tolerability of the IV formulation was evaluated in a pilot phase with a lower dose (65 mg) in 3 subjects prior to the main phase. The main study phase consisted of 17 healthy male volunteers. Plasma concentrations of deferasirox were measured following each treatment, and pharmacokinetic parameters including absolute oral bioavailability were determined. Absolute oral bioavailability of the deferasirox tablets was 70% (90% confidence interval, 62%-80%). Deferasirox was characterized as having a low plasma clearance of 3.53 (± 0.87) L/h. A small volume of distribution of deferasirox at steady state (V_ss) of 14.37 (±2.69 L) was determined, indicating a low tissue distribution.

Single-Dose Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Stimulator BAY 63-2521: An Ascending-Dose Study in Healthy Male Volunteers

Frey, R., Muck, W., Unger, S., Artmeier-Brandt, U., Weimann, G., Wensing, G. — 2008-07-23

The aim of the study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of BAY 63-2521, a new drug in development for pulmonary hypertension. Fifty-eight healthy male volunteers received a single oral dose of BAY 63-2521 (0.25-5 mg) or placebo. No serious adverse events were reported; there were no life-threatening events. Heart rate over 1 minute, an indicator of the effect of a vasodilating agent on the cardiovascular system in healthy subjects, was increased dose dependently versus placebo at BAY 63-2521 doses of 1 to 5 mg (P < .01). Mean arterial and diastolic pressures were decreased versus placebo at doses of 1 mg (P < .05) and 5 mg (P < .01). Systolic pressure was not significantly affected. BAY 63-2521 was readily absorbed and exhibited dose-proportional pharmacokinetics. The pharmacodynamic and pharmacokinetic properties of BAY 63-2521 suggest that it can offer a unique mode of action in the treatment of pulmonary hypertension.

Population Pharmacokinetics of Oseltamivir When Coadministered With Probenecid

Rayner, C. R., Chanu, P., Gieschke, R., Boak, L. M., Jonsson, E. N. — 2008-07-23

Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir–probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir–probenecid combination is used.

Pharmacokinetic Interaction Between Efavirenz and Carbamazepine After Multiple-Dose Administration in Healthy Subjects

Ji, P., Damle, B., Xie, J., Unger, S. E., Grasela, D. M., Kaul, S. — 2008-07-23

The effect of efavirenz on the pharmacokinetics of carbamazepine and vice versa was investigated in adult healthy subjects in a randomized, open-label, 2-period crossover, multiple-dose study. Subjects were randomized to receive either efavirenz 600 mg qd for 14 days or carbamazepine titrated to 400 mg qd for 21 days followed with both drugs for another 21 or 14 days. The pharmacokinetics was evaluated for efavirenz, carbamazepine, and the major metabolite of carbamazepine, carbamazepine-10,11-epoxide. Coadministration of carbamazepine with efavirenz significantly reduced the exposure of efavirenz (geometric mean ratios [90% confidence interval]: area of plasma concentration-time curve during the dosing interval of 24 hours [AUC], 0.64 [0.60-0.68]; maximum plasma concentration [C_max], 0.79 [0.74, 0.85]) and carbamazepine (AUC, 0.73 [0.67-0.80]; C_max, 0.80 [0.76, 0.85]) but had minimal impact on the exposure of carbamazepine-10,11-epoxide (AUC, 0.99 [0.85-1.15]; C_max, 1.05 [0.91, 1.22]). In summary, a 2-way pharmacokinetic interaction between efavirenz and carbamazepine was demonstrated in this study.

Probenecid, but Not Cystic Fibrosis, Alters the Total and Renal Clearance of Fexofenadine

2008-07-23

This study aims to evaluate renal P-glycoprotein (P-gp) activity in patients with cystic fibrosis. P-gp efflux activity in peripheral T cells was measured by flow cytometry in 10 cystic fibrosis and 15 healthy volunteers. Eight cystic fibrosis patients and 8 healthy volunteers were recruited into a crossover pharmacokinetic study in which participants received 180 mg fexofenadine with or without 1 g probenecid twice a day. Genotyping was performed for ABCB1 C1236T, G2677T, and C3435T. P-gp efflux activity in peripheral T cells was not significantly different between cystic fibrosis patients and healthy volunteers. No difference in fexofenadine pharmacokinetic parameters was observed between cystic fibrosis patients and healthy volunteers when fexofenadine was administered with or without probenecid. Coadministration of probenecid significantly increased fexofenadine AUC and decreased the cumulative urinary excretion, total body clearance, and renal clearance. ABCB1 3435 C/T carriers showed increased basal P-gp activity in CD4+ and CD8+ T cells, increased R123-induced efflux activity in CD4+ T cell, and decreased fexofenadine AUC. Fexofenadine disposition and P-gp efflux activity in peripheral T cells was similar between cystic fibrosis patients and healthy volunteers. Probenecid administration significantly reduced the total body and renal clearance of fexofenadine. ABCB1 3435 C/T was associated with an elevated efflux activity compared with C/C subjects.

Pharmacokinetics, Efficacy, and Tolerability of Eslicarbazepine Acetate in Children and Adolescents With Epilepsy

2008-07-23

This study investigates the pharmacokinetics of eslicarbazepine acetate (ESL), a new voltage-gated sodium channel blocker, in epileptic children aged 2 to 7 years (n = 11) and 7 to 11 years (n = 8) and adolescents aged 12 to 17 years (n = 10). The study explores ESL efficacy and tolerability. Patients were treated with ESL once-daily doses of 5 mg/kg/day on weeks 1 to 4, 15 mg/kg/day on weeks 5 to 8, and 30 mg/kg/day (or 1800 mg/day, whichever was less) on weeks 9 to 12. At the end of each 4-week period, a 24-hour pharmacokinetic profiling was performed. Similar to adults, ESL was rapidly metabolized to eslicarbazepine. In all age groups, eslicarbazepine peak concentrations were reached 0.5 hour to 3 hours after ESL dosing, and C_max and AUC_0-24 were dose proportional. Eslicarbazepine C_max was similar between age groups following administration of identical ESL dose/kg, but AUC_0-24 depended on age due to a faster plasma clearance of eslicarbazepine in younger children compared with adolescents. R-licarbazepine and oxcarbazepine were minor metabolites. A dose-dependent decrease in seizure frequency was observed in children aged 2 to 7 years and adolescents aged 12 to 17 years but not in children aged 7 to 11 years. One patient in each group became seizure free. ESL was generally well tolerated.

Single-Dose Pharmacokinetics of Roflumilast in Children and Adolescents

2008-07-23

Roflumilast is an orally administered phosphodiesterase 4 inhibitor that has potential for use in pediatric patients with asthma. The pharmacokinetics of roflumilast and roflumilast N-oxide were examined in adolescents and children with stable mild to moderate asthma in an open-label crossover study with age-stratification and 2 treatment periods (100-µg dose in period 1, 250-µg dose in period 2) separated by a washout period. Plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using standard noncompartmental methods and compared between study groups and within the entire cohort. Roflumilast was well tolerated. Linear relationships were evident for dose and area under the plasma drug concentration–time curve extrapolated to infinity for both roflumilast (r² = 0.36, P < .01) and roflumilast N-oxide (r² = 0.39, P < .01). With the exception of dose-normalized maximum plasma concentration (mean 1.1 and 0.8 µg/L per 1 µg/kg dose for adolescents and children, respectively), pharmacokinetic parameters for roflumilast and roflumilast N-oxide were not different between age groups and were similar to adults.

The Effect of Oral Contraceptives on the Pharmacokinetics of Melatonin in Healthy Subjects With CYP1A2 g.-163C>A Polymorphism

Hilli, J., Korhonen, T., Turpeinen, M., Hokkanen, J., Mattila, S., Laine, K. — 2008-07-23

The effect of oral contraceptives (OCs) on melatonin metabolism was studied in 29 subjects genotyped for CYP1A2 SNP g.-163C>A polymorphism. Plasma melatonin and 6-OH-melatonin concentrations were measured after a 6-mg dose of melatonin using a validated liquid chromatography/mass spectrometry method. The mean melatonin AUC and C_max values were 4- to 5-fold higher in OC users than in non-OC users (P < .0001), whereas the weight-adjusted clearance was significantly lower in OC users (P < .0001). No significant difference in melatonin pharmacokinetics between the genotypes and no additional effect by the genotype on the OC-induced increase in melatonin exposure were evident. Melatonin exposure had no significant effect on the subjects' state of alertness. In conclusion, a significant inhibitory effect of OCs on the CYP1A2-catalyzed melatonin metabolism was seen; thereby, OC use can alter CYP1A2-phenotyping results.

Acyclovir Bioavailability in Patients With Acute Myelogenous Leukemia Treated With Daunorubicin and Cytarabine

Sitar, D. S., Aoki, F. Y., Bow, E. J. — 2008-07-23

A Lesson in Moderation: Applying Pharmacodynamics to Clarify the Relationship Between Thiazolidinediones and Adverse Vascular Outcomes in Type 2 Diabetes

Lehmann, D. F., Lohray, B. B. — 2008-07-23

Editorial

Arya, V. — 2008-06-30

Globalization of Quantitative Pharmacology: First International Symposium of Quantitative Pharmacology in Drug Development and Regulation

Barrett, J. S., Shi, J., Xie, H.-t., Huang, X.-h., Fossler, M. J., Sun, R.-y. — 2008-06-30

The First International Symposium on Quantitative Pharmacology in Drug Development and Regulatory Sciences was held this past October in Nanjing, China, marking the first time scientists from around the globe gathered to discuss topics related to quantitative pharmacology in the Far East. With the recent trend toward global drug development and clinical trials in nontraditional countries, China has been regarded by many as the next frontier for the pharmaceutical industry. Quantitative pharmacology embraces all phases of pharmaceutical research and development, providing a mechanism to bridge decision making from one phase of development to the next, and it facilitates multidisciplinary partnerships through the assembly of both data and models that describe complex biological, biopharmaceutic, and clinical settings. Efforts in China are at an early stage, but it is clear that Chinese scientists embrace the discipline and are keen to promote this methodology in the registration of new drugs in China. While challenges exist, they represent an exciting area of future collaboration.

Novel Trial Design: A Report From the 19th Frontiers Symposium of ACCP

Ameer, B. — 2008-06-30

Novel approaches to drug development along with incentives to reward risk undertaken during early drug development have been proposed to improve the medical product development process. The American College of Clinical Pharmacology held its 19th Frontiers Symposium in mid-2007 to provide a forum to share new knowledge about disease progression models and adaptive and other novel trial designs. These topics reflect the changing paradigm of drug development and regulatory innovation as outlined in the Food and Drug Administration's Critical Path Initiative. This meeting report summarizes some of the presentations and panel discussions among academic, industrial, and regulatory participants regarding clinical trial design, including adaptive Bayesian approaches.

Effects of Aliskiren, a Direct Renin Inhibitor, on Cardiac Repolarization and Conduction in Healthy Subjects

2008-06-30

This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (≤1%) were similar or lower than placebo (≤4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

An Improved Approach for Confirmatory Phase III Population Pharmacokinetic Analysis

Hu, C., Zhou, H. — 2008-06-30

In contrast to the traditional extensive exploratory approach, the authors propose a confirmatory approach to phase III population pharmacokinetics for regulatory submissions. In their approach, they recommend a prespecified primary analysis based on phase I/II data and phase III study design. Their approach also incorporates several specific sensitivity analyses to evaluate the robustness of the conclusions. According to statistical rationale, this approach eliminates certain biases that may occur in the estimated covariate effects, thereby precluding potentially unnecessary dosing adjustments and allowing for more accurate assessments of ambiguity in the results. Because exploration is vastly reduced, the analysis time is also substantially shortened. The proposed analyses are relatively easy to implement, although careful and prospective planning is required. Applications of the approach are provided, including 2 phase III analyses for regulatory submissions. Differences between the proposed approach and the commonly used extensive exploratory analyses submitted to regulatory agencies were small and consistent with practical expectations.

Evaluation of Population Pharmacokinetics and Exposure-Response Relationship With Coadministration of Amlodipine Besylate and Olmesartan Medoxomil

2008-06-30

Population pharmacokinetic models for amlodipine and olmesartan were developed using data collected from 4 phase I studies in healthy volunteers and 1 phase III study in subjects with mild to severe hypertension. A 2-compartment and a 1-compartment model best described the pharmacokinetics of olmesartan and amlodipine, respectively; both agents were characterized by first-order elimination/absorption and an absorption time lag. The analysis shows that neither agent had a clinically significant impact on the clearance of the other. The impact of covariates on the clearance of olmesartan and amlodipine was similar after coadministration of amlodipine besylate and olmesartan medoxomil as separate entities or as a fixed-dose combination compared with monotherapy. The effect of exposure to amlodipine and olmesartan on the change in trough seated diastolic blood pressure was best described by linear and maximum effect (E_max) models, respectively. Black race was the most important covariate in the exposure-response model, decreasing the maximal possible effect of olmesartan on blood pressure while increasing the effect of amlodipine, without influencing pharmacokinetic parameters. The drug effect of combination therapy was defined on the basis of exposure to both compounds and was greater than the effect of monotherapy with either agent.

Population Pharmacokinetic Modeling of Epoetin Delta in Pediatric Patients With Chronic Kidney Disease

Knebel, W., Palmen, M., Dowell, J. A., Gastonguay, M. — 2008-06-30

This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0.268 L/h), central volume of distribution (1.03 L), absorption rate constant (0.0554 h^–1), and bioavailability (0.708) for a 35-kg male ≤10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.

PhRMA White Paper on ADME Pharmacogenomics

2008-06-30

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross-industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003-2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug-metabolizing enzymes and transporters most relevant to the pharmaceutical industry.

New Era in Drug Interaction Evaluation: US Food and Drug Administration Update on CYP Enzymes, Transporters, and the Guidance Process

2008-05-28

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling.

Limitations of Using a Single Postdose Midazolam Concentration to Predict CYP3A-Mediated Drug Interactions

2008-05-28

Midazolam is a common probe used to predict CYP3A activity, but multiple blood samples are necessary to determine midazolam's area under the concentration-time curve (AUC). As such, single sampling strategies have been examined. The purpose of this study was to assess the ability of single midazolam concentrations to predict midazolam AUC in the presence and absence of CYP3A modulation by Ginkgo biloba extract (GBE). Subjects received oral midazolam 8 mg before and after 28 days of GBE administration. Postdose blood samples were collected during both study periods and midazolam AUC determined. Linear regression was used to generate measures of predictive performance for each midazolam concentration. The geometric mean ratio (90% confidence intervals) of midazolam AUC_0- post-GBE/AUC_0- pre-GBE was 0.66 (0.49-0.84) (P = .03). Before and after GBE administration, optimal midazolam sampling times were identified at 3.5 to 5 hours and 2 to 3 hours, respectively. Single midazolam concentrations between 2 and 5 hours correctly predicted the reduction in midazolam AUC following GBE exposure, but confidence intervals were generally wide. Intersubject variability in CYP3A activity (either inherent or from drug administration) alters the prediction of optimal midazolam sampling times; therefore, midazolam AUC is preferred for assessing CYP3A activity in drug-drug interaction studies.

Population Pharmacokinetics of Infliximab in Patients With Ankylosing Spondylitis

2008-05-28

The population pharmacokinetics of infliximab were characterized in patients with active ankylosing spondylitis (n = 274). Serum infliximab concentration data, from a 2-year period, were analyzed using NONMEM. A 2-compartment linear pharmacokinetic model was chosen to describe the pharmacokinetic characteristics of infliximab in serum. Population estimates (typical value ± standard error) were obtained from the final covariate model: clearance (CL: 0.273 ± 0.007 L/day), volume of distribution in the central compartment (V₁: 3.06 ± 0.057 L), intercompartment clearance (Q: 1.72 ± 0.48 L/day), and volume of distribution in the peripheral compartment (V₂: 2.94 ± 0.17 L). Interindividual variability for CL and V₁ was 34.1% and 17.5%, respectively. White blood cell count at baseline and the antibody-to-infliximab status were significant covariates to CL; body surface area and sex were significant covariates to V₁. The CL for patients with a positive antibody-to-infliximab status was estimated to be 41.9% to 76.7% higher than for the remaining patients. Other covariates (baseline disease activity and the concomitant medication use of prednisolone, omeprazole, nonsteroidal anti-inflammatory drugs, or analgesics) did not affect infliximab pharmacokinetics. The development of antibodies to infliximab was associated with accelerated infliximab clearance and may represent a potential underlying mechanism for an inadequate response, or loss of response, to infliximab treatment.

Population Exposure-Response Modeling of Metformin in Patients With Type 2 Diabetes Mellitus

2008-05-28

The exposure-response properties of metformin were characterized in 12 subjects with type 2 diabetes mellitus. The time course of drug concentration and effects on fasting plasma glucose and lactic acid concentrations were used from a study in which subjects received 500 mg of metformin twice daily for 5 days followed by 850 mg twice daily for 5 days. Pharmacokinetic sampling included morning trough concentrations obtained on days 7 to 9 and rich sampling (15 time points) on day 10. Fasting plasma glucose and lactic acid concentrations were measured on days 0 to 10 and served as biomarkers of therapeutic effect and tolerability, respectively. A population pharmacokinetic/pharmacodynamic analysis was conducted using nonlinear mixed effects modeling. Metformin pharmacokinetics were described using a 1-compartment model with first-order absorption. Population mean estimates (relative standard error [RSE]) of clearance (CL/F) and volume of distribution were 79.0 L·h^–1 (6.8%) and 648 L (13.8%), respectively. Covariate analyses revealed that creatinine clearance (CL_CR) significantly influenced metformin CL/F [CL/F = 79.0·(CL_CR/80)^0.822]. An indirect response model was applied to describe the antihyperglycemic effect of metformin. Population mean estimates (RSE) of baseline fasting plasma glucose and the drug concentration producing half-maximal effect were 241 mg·dL^–1 (4.6%) and 4.23 mg·L^–1 (31.0%). An empirical linear model was used to describe a slight progressive increase in fasting lactic acid during metformin treatment with an estimated slope coefficient (RSE) of 0.0005 mM·mL·ng^–1 (38.1%). Model evaluation by predictive check and nonparametric bootstrap analysis suggested that the proposed model is robust, and parameter values were estimated with good precision. Simulations suggested that the clinical utility of metformin was maintained over the dose range evaluated with respect to fasting plasma glucose and lactic acid response.

Population Pharmacokinetic and Pharmacodynamic Analysis of Pegloticase in Subjects With Hyperuricemia and Treatment-Failure Gout

2008-05-28

Pegloticase is designed to convert urate into the easily excretable allantoin to treat hyperuricemia in gout. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4- and 8-mg doses or every 4 weeks at 8- or 12-mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and covariates were investigated (age, gender, race, body weight, ideal body weight, and antibody response). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1-compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (E_max) function. Pegloticase suppressed uric acid levels up to 83%. Weight only affected clearance and volume of distribution. No covariates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2-hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.

A Note on Population Analysis of Dissolution-Absorption Models Using the Inverse Gaussian Function

Wang, J., Weiss, M., D'Argenio, D. Z. — 2008-05-28

Because conventional absorption models often fail to describe plasma concentration–time profiles following oral administration, empirical input functions such as the inverse Gaussian function have been successfully used. The purpose of this note is to extend this model by adding a first-order absorption process and to demonstrate the application of population analysis using maximum likelihood estimation via the EM algorithm (implemented in ADAPT 5). In one example, the analysis of bioavailability data of an extended-release formulation, as well as the mean dissolution times estimated in vivo and in vitro with the use of the inverse Gaussian function, is well in accordance, suggesting that the inverse Gaussian function indeed accounts for the in vivo dissolution process. In the other example, the kinetics of trapidil in patients with liver disease, the absorption/dissolution parameters are characterized by a high interindividual variability. Adding a first-order absorption process to the inverse Gaussian function improved the fit in both cases.

Raltegravir Thorough QT/QTc Study: A Single Supratherapeutic Dose of Raltegravir Does Not Prolong the QTcF Interval

2008-05-28

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC₉₅ = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C_max of ~20 µM raltegravir was attained, ~4-fold higher than the C_max at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.

Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of Taranabant, a Novel Selective Cannabinoid-1 Receptor Inverse Agonist, in Healthy Male Volunteers

2008-05-28

Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t_max of 1.0 to 2.0 hours and a t_1/2 of approximately 74 to 104 hours. Moderate accumulation was observed in C_max (1.18- to 1.40-fold) and AUC_{0-24 h} (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC_{0-24 h} and C_max of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.

Comparative Inhibitory Activity of Etoricoxib, Celecoxib, and Diclofenac on COX-2 Versus COX-1 in Healthy Subjects

2008-05-28

We determined cyclo-oxygenase-1 and cyclo-oxygenase-2 inhibition in healthy middle-aged subjects (41-65 years) randomly assigned to four 7-day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double-blind, randomized, 4-period crossover study. Maximum inhibition of thromboxane B₂ (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E₂ in whole blood (cyclo-oxygenase-2 activity) was assessed on day 7 (0-24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B₂ versus each comparator (P < .001); placebo 2.4% (95% confidence interval: –8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E₂ synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo-oxygenase-1 and cyclo-oxygenase-2, whereas etoricoxib and celecoxib significantly inhibit cyclo-oxygenase-2 and do not substantially inhibit cyclo-oxygenase-1.

Cutaneous Pharmacodynamics of a Toll-Like Receptor 7 Agonist, 852A, in Humans

Astry, C., Birmachu, W., Harrison, L. I., Meng, T.-C. — 2008-05-28

852A is a specific toll-like receptor 7 (TLR7) agonist. Thirty-two healthy adults (8 subjects per group) received two 1-g topical applications over 400 cm², separated by ≥ 5 days, of 852A 0.01% followed by vehicle, vehicle followed by 852A 0.1%, 852A 0.3% followed by vehicle, or vehicle followed by 852A 1.0%. Systemic absorption was minimal as 852A was not quantifiable in any serum sample up to 24 hours postadministration and was only quantifiable at 24 hours in the urine of 4 of 8 subjects after application of 852A 1.0%. No systemic adverse events were associated with drug treatment. Gene expression analysis from application site biopsies showed a ≥2-fold increase in expression for 40 genes in at least 2 subjects. CXCL9/MIG (8/32 subjects), CCL2/MCP1 (7/32), and OAS3 (5/32) were most frequently increased, followed by other type I interferon-inducible genes. Cluster analysis of the genes with a ≥2-fold increase did not reveal a definitive pattern with respect to 852A concentration or time of biopsy. Overall, single topical application of 852A up to 1.0% was well tolerated. Data gathered from these subjects are suggestive that 852A can produce increases in local gene expression consistent with TLR7 stimulation.

Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus

Wang, Y., Yin, O. Q. P., Graf, P., Kisicki, J. C., Schran, H. — 2008-05-28

Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of midostaurin following multiple oral doses of midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100-mg dose in patients with diabetes mellitus (n = 9-13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (C_max and AUC_0-) of midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2-fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%-50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration-time pattern as midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high-fat meal was found to significantly increase the C_max and AUC_{0-12 h} of midostaurin by 1.5-fold (P = .04) and 1.8-fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment-related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150-mg/day dose level.