Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study
Name
Tannenbaum_Biphasic elimination.pdf
Size
619.23 KB
Format
Adobe PDF
Checksum (MD5)
346aa8b31a2d99b19b6856925ee80359
Author(s)
Chen, Jianmeng
Flexner, Charles
Liberman, Rosa G.
Skipper, Paul L.
Louissaint, Nicolette A.
Hendrix, Craig W.
Fuchs, Edward J.
Tannenbaum, Steven Robert
Date Issued
December 2012
Journal
JAIDS Journal of Acquired Immune Deficiency Syndromes
Publisher
Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins
Citation
Chen, Jianmeng, Charles Flexner, Rosa G. Liberman, Paul L. Skipper, Nicolette A. Louissaint, Steven R. Tannenbaum, Craig W. Hendrix, and Edward J. Fuchs. “Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study.” JAIDS Journal of Acquired Immune Deficiency Syndromes 61, no. 5 (2012): 593–599.
Version
Author's final manuscript
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 [superscript 14]C-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[superscript +] cells were measured by accelerator mass spectrometry.
Results: The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg–300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4[superscript +] cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4[superscript +] 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. School of Science
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1097/QAI.0b013e3182717c98
