PHARMACOKINETICS, ABSOLUTE BIOAVAILABILITY, AND ABSORPTION CHARACTERISTICS OF LAMIVUDINE

Lamivudine is a novel cytosine nucleoside analog, reverse transcriptas e inhibitor that has shown activity against human immunodeficiency vir us (HIV) types 1 and 2 and hepatitis B virus in vitro. This study was conducted to compare the absolute bioavailability, pharmacokinetics, a nd absorption characteristics of oral solution, 100-mg capsule, and 10 0-mg tablet formulations of lamivudine with those of intravenous lamiv udine. Twelve patients with HIV were enrolled in a single-center, rand omized, open-label, four-way crossover study. Treatment arms consisted of 100 mg intravenous lamivudine (administered over 1 hour), 100 mg o ral lamivudine (1 mg/mL), a 100-mg capsule, and a 100-mg tablet, each followed by a 3- to 14-day washout period. Serial blood samples over 2 4 hours were obtained after each dose administration. Serum concentrat ion data were analyzed to determine pharmacokinetic parameter estimate s including area under the curve (AUG), terminal half-life (t(1/2)), m ean residence time (MRT) for each formulation, systemic clearance, ora l clearance, and apparent volume of distribution (Vd). Absolute bioava ilability and in vivo mean absorption time (MAT) and mean dissolution time (MDT) were calculated for the oral formulations. Deconvolution te chniques were used to calculate the input rate for the oral solution, capsule, and tablet. The two one-sided t test was used to determine bi oequivalency among oral formulations with respect to logarithmic trans formed estimates of AUC and maximum peak concentration (C-max). Mean ( CV) systemic clearance and Vd(ss) after intravenous administration of lamivudine were 22.6 L/h (15%) and 99 L (28%), respectively; mean t(1/ 2) ranged from 8.41 to 9.11 hours for all formulations; and MRT ranged from 4.42 to 5.77 hours for all formulations. Mean absolute bioavaila bility ranged from 86% to 88% for the oral solution, capsule, and tabl et. All oral formulations solution, and MDT was 0.03 and -0.11 hours f or the capsule and oral solution, respectively. The oral formulations of lamivudine examined in this study demonstrated acceptable bioavaila bility for oral administration. The solid oral formulations (capsule a nd tablet) show rapid dissolution properties with an absorption rate s imilar to or exceeding those observed with the oral solution. This sug gests that dissolution is not on important factor for the fate of abso rption of lamivudine. The use of deconvolution techniques using PCDCON provides valuable insight into the absorption characteristics of lami vudine.