Zidovudine triphosphate and lamivudine triphosphate concentration–response relationships in HIV-infected persons

Abstract

These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.

High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

“…These findings were in agreement with previous studies showing a decrease in plasma AZT concentrations with the age of newborns (12,39) and proved that the same observation was true at the intracellular level. Plasma AZT levels, collected 4 to 6 h after dosing and measured here during the first 2 weeks (range, 89.1 to 1,290 ng/ml), are in agreement with those previously reported for neonates (trough concentration of around 400 ng/ml at birth) (39) and are higher than those measured in adults (trough concentration, 100 to 300 ng/ml) (2,26,27,52). Intracellular AZT-MP/TP measurements in newborns are reported here for the first time.…”

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open‐Label, Randomized Study

“…Finally, this study measured plasma lamivudine concentrations rather than intracellular concentrations of the pharmacologically active triphosphate metabolite. Studies have shown relationships between intracellular concentrations of lamivudine triphosphate and the rate of decline in HIV viral load and rise in CD4+ cell count with treatment; however, sample collection and measurement of intracellular triphosphate is technically more challenging and less amenable to routine patient care than measurement of plasma concentrations 21. Therefore, the plasma lamivudine AUC is commonly used as a surrogate measure of intracellular concentration and antiviral activity, even though the relationship between plasma lamivudine concentrations and intracellular active triphosphate concentrations is complex,21 and makes it difficult to define the clinical significance of a plasma PK drug interaction.…”

p16INK4a, a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV‐Infected Subjects

“…Modest evidence suggests that cellular activation may increase intracellular phosphorylase activity in the elderly,10 potentially resulting in increased toxicity 11. The active intracellular phosphorylated forms of TFV and FTC have not been studied in older patients 12, 13, 14…”