Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study

Jianmeng Chen, Charles Flexner, Rosa G. Liberman, Paul L. Skipper, Nicolette A. Louissaint, Steven R. Tannenbaum, Craig W. Hendrix, Edward J. Fuchs

Research output: Contribution to journalArticle

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 μg) 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 mg-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.

Original languageEnglish (US)
Pages (from-to)593-599
Number of pages7
JournalJournal of Acquired Immune Deficiency Syndromes
Volume61
Issue number5
DOIs
StatePublished - Dec 15 2012

Keywords

  • Microdose
  • Pharmacokinetics
  • Tenofovir-diphosphate

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

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