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Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Jian-Meng Chen, C. Flexner, R. G. Liberman, P. Skipper, N. Louissaint, C. Hendrix, E. Fuchs, S. Tannenbaum

Journal of Acquired Immune Deficiency Syndromes December 1, 2012 DOI: 10.1097/qai.0b013e3182717c98 (opens in new tab)

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AI-extracted from the abstract
Characteristics Observational pharmacokinetic study Peer reviewed
Population Healthy volunteers
Interventions Zidovudine (ZDV) Tenofovir disoproxil fumarate
Dose 100 µg microdose; 300 mg standard dose
Measures accelerator mass spectrometry
Topics Microdosing
Key findings Intracellular ZDV-triphosphate increased less than proportionally from 100 µg to 300 mg, indicating a rate-limiting phosphorylation step, whereas tenofovir-diphosphate pharmacokinetics were linear over the same range. ZDV-triphosphate was lower in CD4+ cells than in total PBMCs, while tenofovir-diphosphate did not differ between cell types. The authors suggest accelerator mass spectrometry may predict active intracellular metabolite pharmacokinetics, though nonlinearity may occur with some drugs.

Abstract

Objective:Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design:We administered a microdose (100 &mgr;g) of 14C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4+ cells were measured by accelerator mass spectrometry. Results:The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 &mgr;g–300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4+ cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4+ cells and PBMCs. Conclusions:Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.

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