There is no significant interaction between tenofovir and didanosine in human PBMCs as determined by the extent of formation of the phosphorylated anabolites. This suggests that adjusting didanosine dosage, when given with tenofovir, to achieve similar didanosine plasma concentrations, may be sufficient to accommodate the systemic drug interaction.

These data suggest that HIV-1 circulating in blood monocytes represents diverse HIV-1 with multiple phenotypes and that MDMS-R5 viruses may play an important role in infection with and persistence of HIV-1 within the monocyte/macrophage lineage.

The pharmacologic variability of nucleoside reverse transcriptase inhibitors such as lamivudine (3TC) includes not only systemic pharmacokinetic variability but also interindividual differences in cellular transport and metabolism. A modeling strategy linking laboratory studies of intracellular 3TC disposition with clinical studies in adolescent patients is described. Data from ex vivo laboratory experiments using peripheral blood mononuclear cells (PBMCs) from uninfected human subjects were first used to determine a model and population parameter estimates for 3TC cellular metabolism. Clinical study data from human immunodeficiency virus type 1-infected adolescents were then used in a Bayesian population analysis, together with the prior information from the ex vivo analysis, to develop a population model for 3TC systemic kinetics and cellular kinetics in PBMCs from patients during chronic therapy. The laboratory results demonstrate that the phosphorylation of 3TC is saturable under clinically relevant concentrations, that there is a rapid equilibrium between 3TC monophosphate and diphosphate and between 3TC diphosphate and triphosphate, and that 3TC triphosphate is recycled to 3TC monophosphate through a 3TC metabolite that remains to be definitively characterized. The resulting population model shows substantial interindividual variability in the cellular kinetics of 3TC with population coefficients of variation for model parameters ranging from 47 to 87%. This two-step ex vivo/clinical modeling approach using Bayesian population modeling of 3TC that links laboratory and clinical data has potential application for other drugs whose intracellular pharmacology is a major determinant of activity and/or toxicity.Highly potent combination antiretroviral therapy has significantly reduced the mortality and morbidity of individuals infected with human immunodeficiency virus type 1 (HIV-1) (14,29). Because of pharmacologic, virologic, immunologic, and behavioral differences among individuals, however, not all patients receive the optimal therapeutic benefit from antiretroviral therapy (8). Initial therapy for HIV-1-infected patients usually consists of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine [ZDV] and lamivudine [3TC]) and either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor (5). Although initial therapy is effective for a high proportion of patients, treatment failure and toxicity remain substantial problems, and pharmacokinetic variability can be an important contributing factor. Studies have shown that individualized therapy that controls for the systemic pharmacokinetic variability of indinavir, ZDV, and 3TC can improve the virological outcome relative to that of conventional fixed-dose therapy (9).For NRTIs like ZDV and 3TC, pharmacologic variability includes not only systemic pharmacokinetic variability but also interindividual differences in cellular transport and metabolism. All NRTIs must cross the cell membrane and undergo stepwise phosp...