Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formulation versus coadministration of the individual products.
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 AUC(0-t), AUC(0-infinity), and C(max) 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.
Marier
J F
JF
Vice President, Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Laboratories Ltd, Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon-122001, Haryana, India.
Dimarco
M
M
Guilbaud
R
R
Dodard
C
C
Morelli
G
G
Tippabhotla
S K
SK
Singla
A K
AK
Thudi
N R
NR
Monif
T
T
D000293:Adolescent; D000328:Adult; D003430:Cross-Sectional Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000191:economics; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000191:economics / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects / Q000191:economics / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000191:economics / Q000493:pharmacokinetics*; D015215:Zidovudine / Q000009:adverse effects / Q000191:economics / Q000493:pharmacokinetics*
D004338:Drug Combinations; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019829:Nevirapine