The Journal of Clinical Pharmacology current issue

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