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Intracellular Pharmacokinetics of Tenofovir Diphosphate, Carbovir Triphosphate, and Lamivudine Triphosphate in Patients Receiving Triple-Nucleoside Regimens

Hawkins, Trevor MD*; Veikley, Wenoah AC, RN*; St. Claire, Robert L III PhD; Guyer, Bill PharmD; Clark, Nicole PhD; Kearney, Brian P PharmD

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1st, 2005 - Volume 39 - Issue 4 - p 406-411
doi: 10.1097/01.qai.0000167155.44980.e8
Clinical Science

Objective: To evaluate the potential for a pharmacologic mechanism to explain suboptimal virologic responses observed in a triple-nucleoside only regimen containing tenofovir disoproxil fumarate (TDF), abacavir (ABC), and lamivudine (3TC).

Methods: This was a prospective evaluation of intracellular concentrations and pharmacokinetics of tenofovir diphosphate (TFV-DP), carbovir triphosphate (CBV-TP), and lamivudine triphosphate (3TC-TP) in patients on triple-nucleoside regimens. Fifteen patients on a stable TDF plus ABC plus a third nucleoside reverse transcriptase (RT) inhibitor (3TC [n = 13], stavudine [n = 2]) regimen discontinued TDF or ABC, replacing it with a nonnucleoside RT inhibitor or protease inhibitor. Peripheral blood mononuclear cells were collected after the last dose of TDF or ABC at baseline and over 12 to 96 hours as well as at days 14 and 28 after discontinuation. Nucleotide concentrations were measured directly using liquid chromatography with tandem mass spectrometry; changes after ABC or TDF discontinuation would provide evidence of an intracellular drug interaction.

Results: Intracellular nucleotide concentrations of the continued drugs were unaffected when TDF or ABC was discontinued. Intracellular levels of TFV-DP exhibited less inter- and intrapatient variability than CBV-TP or 3TC-TP. TFV-DP also had persistent intracellular levels on TDF discontinuation (median half-life of 150 hours, range: 60 to >175 hours). CBV-TP concentrations fell to below the limit of detection in all patients by 72 hours after the last ABC dose in accordance with a median half-life of 18 hours (range: 12-19 hours).

Conclusions: An intracellular drug interaction does not explain the suboptimal viral response in patients treated with the nucleoside-only regimen of TDF, ABC, and 3TC.

From the *Southwest CARE Center, Santa Fe, NM; †Gilead Sciences, Inc., Durham, NC; and ‡Gilead Sciences, Inc., Foster City, CA.

Received for publication December 20, 2004; accepted March 29, 2005.

Technical and financial support for this study was provided by Gilead Sciences, Inc.

Reprints: Trevor Hawkins, Southwest CARE Center, 649, Harkle Rd, Ste E, Santa Fe, NM 87505 (e-mail:

© 2005 Lippincott Williams & Wilkins, Inc.