Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir.
OBJECTIVE
Lopinavir/ritonavir (LPV/r) and tenofovir disoproxil fumarate (TDF) are frequently used antiretrovirals. A pharmacokinetic study in healthy volunteers was conducted to assess the potential for a drug interaction between these agents.


METHODS
This was a 36-day, multiple-dose, drug-drug interaction study of TDF and lopinavir/ritonavir (LPV/r). Subjects received TDF alone for 7 days, followed by 14 days each of TDF plus LPV/r and LPV/r alone in a randomized manner. Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35. LPV/r and tenofovir plasma/serum concentrations were measured by high-performance liquid chromatography/mass spectometry (MS)/MS. Geometric mean ratios and 90% confidence intervals of pharmacokinetic parameters for tenofovir, LPV, and ritonavir (RTV) were estimated using analysis of variance and compared with the no-effect criterion for pharmacokinetic equivalence.


RESULTS
Tenofovir measurements with an area under the concentration-time curve over the dosing interval, maximum concentration, and concentration at the end of the dosing interval (Ctau) were 32%, 15%, and 51% higher, respectively, when TDF was coadministered with LPV/r (n = 24). LPV and RTV pharmacokinetics, including Ctau, were unaffected by TDF (n = 24). Clinical estimates of renal function were unaffected by administration of TDF alone or with LPV/r.


CONCLUSIONS
Coadministration of TDF with LPV/r resulted in increased tenofovir exposures at steady state, possibly through increased absorption. This increase is not believed to be clinically relevant based on the safety and efficacy of TDF plus LPV/r-containing regimens in HIV-infected patients in long-term controlled clinical trials.
Kearney
Brian P
BP
Gilead Sciences, Inc., Foster City, CA, USA. bkearney@gilead.com
Mathias
Anita
A
Mittan
Angelique
A
Sayre
John
J
Ebrahimi
Ramin
R
Cheng
Andrew K
AK
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D063065:Organophosphonates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000097:blood / Q000494:pharmacology*; D019258:Saquinavir / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068698:Tenofovir
D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; D019258:Saquinavir; D019438:Ritonavir