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

Br J Clin Pharmacol. 2008 Apr;65 Suppl 1(Suppl 1):27-37. doi: 10.1111/j.1365-2125.2008.03133.x.

Abstract

Aims: To evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacokinetics*
  • Antifungal Agents / adverse effects
  • Antifungal Agents / pharmacokinetics*
  • Atazanavir Sulfate
  • CCR5 Receptor Antagonists*
  • Cyclohexanes / adverse effects
  • Cyclohexanes / pharmacokinetics*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors*
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • HIV Infections / drug therapy
  • HIV Protease Inhibitors / adverse effects
  • HIV Protease Inhibitors / pharmacokinetics*
  • Humans
  • Ketoconazole / adverse effects
  • Ketoconazole / pharmacokinetics
  • Male
  • Maraviroc
  • Middle Aged
  • Oligopeptides / adverse effects
  • Oligopeptides / pharmacokinetics
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Saquinavir / adverse effects
  • Saquinavir / pharmacokinetics
  • Statistics as Topic
  • Triazoles / adverse effects
  • Triazoles / pharmacokinetics*

Substances

  • Anti-HIV Agents
  • Antifungal Agents
  • CCR5 Receptor Antagonists
  • Cyclohexanes
  • Cytochrome P-450 CYP3A Inhibitors
  • HIV Protease Inhibitors
  • Oligopeptides
  • Pyridines
  • Triazoles
  • Atazanavir Sulfate
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Saquinavir
  • Maraviroc
  • Ketoconazole