Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir.
Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC(0-4)), the maximum concentration of the drug (C(max)), and the residual concentration of the drug at the end of the dosing interval (C(trough)) for plasma and the AUC(0-4) and C(trough) for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC(0-4) was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C(trough) values for women.
Pruvost
Alain
A
CEA, IBiTec-S, Service de Pharmacologie et d'Immunoanalyse, PC no. 18, F-91191 Gif sur Yvette, France. alain.pruvost@cea.fr
Negredo
Eugènia
E
Théodoro
Frédéric
F
Puig
Jordi
J
Levi
Mikaël
M
Ayen
Rafaela
R
Grassi
Jacques
J
Clotet
Bonaventura
B
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003430:Cross-Sectional Studies; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics; D008137:Longitudinal Studies; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068698:Tenofovir; D016896:Treatment Outcome; D000099227:Abacavir
D000225:Adenine; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D017320:HIV Protease Inhibitors; D019259:Lamivudine; D061466:Lopinavir; D063065:Organophosphonates; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir; D000068698:Tenofovir; D000099227:Abacavir