J Clin Pharmacol
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PHARMACOKINETICS

Pharmacokinetics of Lamivudine, Zidovudine, and Nevirapine Administered as a Fixed-Dose Combination Formulation Versus Coadministration of the Individual Products

J. F. Marier, PhD, M. DiMarco, PhD, R. Guilbaud, MSc, C. Dodard, PhD, G. Morelli, MD, S. K. Tippabhotla, MPharm, A. K. Singla, MPharm, N. R. Thudi, BPharm and T. Monif, PhD

From MDS Pharma Services, St-Laurent (Montréal), Quebec, Canada (J. F. Marier, M. DiMarco, R. Guilbaud, C. Dodard, G. Morelli), Ranbaxy Laboratories Ltd, Gurgaon, Haryana, India (S. K. Tippabhotla, A. K. Singla, T. Monif), and Ranbaxy Pharmaceuticals Canada, Inc, Mississauga, Ontario, Canada (N. R. Thudi). J. F. Marier is currently at Pharsight Corporation, Montréal, Quebec, Canada.

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed-dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open-label, randomized, 2-way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed-dose combination to individual products) and 90% confidence intervals of AUC0-t, AUC0-{infty}, and Cmax for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed-dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed-dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug-related adverse events. The current fixed-dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.

Key Words: pharmacokinetics • fixed-dose combination • lamivudine • zidovudine • nevirapine

Address for correspondence: Tausif Monif, PhD, Vice President, Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Laboratories Ltd, Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon—122 001, Haryana, India.


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