Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens.
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.
Hawkins
Trevor
T
Southwest CARE Center, Santa Fe, NM 87505, USA. thawkins@southwestcare.org
Veikley
Wenoah
W
St Claire
Robert L
RL
Guyer
Bill
B
Clark
Nicole
N
Kearney
Brian P
BP
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015224:Dideoxynucleosides / Q000097:blood / Q000493:pharmacokinetics*; D054306:Dideoxynucleotides; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000097:blood / Q000493:pharmacokinetics*; D011446:Prospective Studies; D000068698:Tenofovir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D054306:Dideoxynucleotides; D063065:Organophosphonates; C417268:lamivudine triphosphate; C057503:carbovir; D019259:Lamivudine; D003570:Cytidine Triphosphate; D000068698:Tenofovir; D000225:Adenine