Addition of saquinavir (SQV) to a regimen of capravirine (CPV) plus lopinavir/ritonavir (LPV/r) does not alter systemic exposure of the antiretrovirals in healthy volunteers
Background: CPV, a novel nonnucleoside reverse transcriptase inhibitor (NNRTI), exhibits potent in vitro activity against HIV variants with RT substitutions including K103N. Clinical trials are investigating CPV in combination with protease inhibitor-containing regimens in NNRTI-experienced and heavily pretreated patients. CPV and protease inhibitors are metabolized by CYP3A4. Previous studies show LPV/r increases CPV 5-fold while CPV causes dose-dependent reduction in LPV of 15 to 40%. CPV alone does not affect SQV. This open-label, multiple-dose study evaluated PK, tolerability, and safety of CPV administered with LPV/r plus SQV in healthy volunteers. Methods: 28 subjects were assigned to receive either CPV 400 mg plus LPV/r 400/100 mg BID or CPV 700 mg plus LPV/r 533/133 mg BID. SQV (hard-gel) 1000 mg BID was added to each regimen using dose escalation to improve tolerability. Trough and serial blood samples were obtained to determine plasma drug concentrations at steady-state. PK analysis was done using noncompartmental methods. Effect of SQV on CPV plus LPV/r was assessed by t-test on log-transformed parameters. Results: 22 subjects (79%) completed the study. Addition of SQV to either dose regimen of CPV plus LPV/r did not alter the geometric mean AUC of CPV or LPV/r. SQV AUC and Cmin were 20.6 mg*h/L and 0.63 mg/L, respectively, in combination with CPV 400 mg plus LPV/r 400/100 mg and 36.6 mg*h/L and 1.33 mg/L, respectively, with CPV 700 mg plus LPV/r 533/133 mg. The most common adverse events (diarrhea, headache, and dysgeusia) occurred at higher incidence with CPV 700 mg plus LPV/r 533/133 mg and SQV 1000 mg BID. Conclusions: Addition of SQV to a regimen of CPV plus LPV/r does not require further dose adjustment of CPV, LPV/r, or SQV. SQV concentrations in combination with both CPV plus LPV/r dose regimens are within the ranges previously reported for ritonavir-boosted SQV regimens.
Raber, S R
S R Raber1, M A Amantea1, J Zhou1, S Piraino1, R Reynolds1, B Hee1, C Ballow2, R Pesano1
1Pfizer Global Research and Development, San Diego, CA, United States; 2Buffalo Clinical Research Center, Buffalo, NY, United States