The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1

Objective: To assess the pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells (PBMC) from patients infected with HIV-1 . Design: Single-center, open-label, randomized, two-period, cross-over study in 10 asymptomatic, antiretroviral-experienced, HIV-1-infected patients wh o had a CD4-t lymphocyte count of 200-500 x 10(6)/l and had received combin ation treatment with lamivudine 150 mg twice a day plus zidovudine 600 mg a day (divided into two or three doses) for greater than or equal to 16 week s prior to study entry. Methods: Patients were randomly assigned to receive lamivudine 150 mg twice a day or lamivudine 300 mg twice a day for 14 days, with at least a 48-h w ashout period between treatments. Serial blood samples were collected over 36 h for determination of lamivudine serum concentrations using liquid chro matography/mass spectrometry and intracellular phosphate PBMC concentration s using high performance liquid chromatography/radioimmunoassay methods. Ph armacokinetic parameters were calculated based on lamivudine and lamivudine anabolite concentration-time data. Results: Intracellular pharmacokinetic parameters were highly variable betw een patients (coefficient of variations approximately 50%). The two regimen s produced lamivudine-total phosphate (totP) values of a similar magnitude. Although the 300-mg regimen tended to produce higher lamivudine-monophosph ate (MP) and -triphosphate (TP) values, differences from values produced by the 150-mg regimen were not statistically significant. As lamivudine dipho sphate (DP) was the predominant anabolite, accounting for 50-55% of lamivud ine-totP (compared with 30-35% for lamivudine-MP and 15-20% for lamivudlne- TP), the conversion of lamivudine-DP to lamivudine-TP can be regarded as th e rate-limiting step. The median lamivudine-TP intracellular half-life (t(1 /2)) for the 150-mg and 300-mg regimens did not differ significantly (15.3 and 16.1 h, respectively). Serum lamivudine pharmacokinetic parameters were consistent with those observed in previous studies in HIV-1-infected patie nts. No apparent linear relationships were observed between lamivudine intr acellular anabolite and serum data. Conclusions: The intracellular pharmacokinetics of lamivudine phosphorylati on in PBMC from asymptomatic HIV-1-infected patients are highly variable an d do not differ statistically between the 150- and 300-mg twice a day regim ens. The variations in intracellular lamivudine-TP concentrations following these two lamivudine dosage regimens are unlikely to result in differences in clinical effect. This was confirmed by the results of a large phase III study in HIV-1-infected patients which showed no differences in HIV-1 RNA or CD4+ lymphocyte counts between the 150- and 300-mg lamivudine regimens i n combination with zidovudine. (C) 1999 Lippincott Williams & Wilkins.