Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers

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Abstract
To evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist. Four open-label, randomized, placebo-controlled studies were conducted in healthy subjects to assess the effect of separate and distinct combinations of CYP3A4 inhibitors on the steady-state pharmacokinetics of maraviroc. Study 1 was a two-way crossover study investigating the influence of saquinavir (SQV; 1200 mg t.i.d.) and ketoconazole (400 mg q.d.) on the pharmacokinetics of maraviroc (100 mg b.i.d.). All subjects received maraviroc for 7 days in both study periods. Cohort 1 subjects also received SQV or placebo and cohort 2 subjects also received ketoconazole or placebo. Study 2 was a parallel-group study including four treatment groups investigating the effects of ritonavir-boosted lopinavir (LPV/r; 400 mg/100 mg b.i.d.), ritonavir-boosted saquinavir (SQV/r; 1000 mg/100 mg b.i.d.), and low-dose ritonavir (RTV; 100 mg b.i.d.) on the steady-state pharmacokinetics of maraviroc (100 mg b.i.d.), and exploring whether maraviroc dose adjustment can compensate for interaction effects. Treatment lasted 28 days and comprised three distinct phases: (i) maraviroc alone on days 1-7; (ii) maraviroc + interactant on days 8-21; and (iii) maraviroc (adjusted dose) + interactant on days 22-28. Study 3 was a two-way crossover study investigating the effects of atazanavir (ATZ; 400 mg q.d.) and ritonavir-boosted atazanavir (ATZ/r; 300 mg/100 mg b.i.d.) on the pharmacokinetics of maraviroc (300 mg b.i.d.). All subjects received maraviroc on days 1-14 of both study periods. Subjects also received ATZ on days 1-7 and ATZ/r on days 8-14 of one treatment period, and placebo on days 1-14 of the other treatment period. Study 4 was a two-way crossover study investigating the effects of ritonavir-boosted tipranavir (TPV/r; 500 mg/200 mg b.i.d.) on the pharmacokinetics of maraviroc (150 mg b.i.d.). Subjects received maraviroc plus TPV/r or placebo on days 1-8. All of the drugs/drug combinations tested (except for TPV/r) increased maraviroc exposure, albeit to different degrees of magnitude. SQV/r caused the largest increase in maraviroc exposure (8.3-fold increase in AUC(tau)), whereas RTV caused the smallest increase in maraviroc exposure (2.6-fold increase in AUC(tau)). Downward adjustment of the maraviroc dose in study 2 during co-administration of HIV protease inhibitors was able to compensate for the interactions. TPV/r had no clinically relevant effect on maraviroc exposure at steady state. There were no treatment-related serious adverse events or discontinuations due to adverse events in any of the studies, and most adverse events were mild or moderate in severity and resolved without intervention. Potent CYP3A4 inhibitors, including ketoconazole and protease inhibitors (except TPV/r), increase maraviroc exposure. Downward adjustment of the maraviroc dose during co-administration with protease inhibitors can compensate for the interaction. TPV/r does not affect the steady-state pharmacokinetics of maraviroc, and hence no dose adjustment would be warranted.