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

Abstract

AIMSTo evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist. METHODSFour 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. RESULTSAll 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 AUCt), whereas RTV caused the smallest increase in maraviroc exposure (2.6-fold increase in AUCt). 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. CONCLUSIONSPotent 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-...

Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

“…In healthy volunteers, coadministration of maraviroc at 300 mg b.i.d. with atazanavir (boosted or unboosted), saquinavir (boosted or unboosted), and lopinavir-ritonavir resulted in a 4-to 10-fold increase in maraviroc exposures over that with maraviroc alone (4). The approximately 4-fold increase in the maraviroc exposure observed in the darunavir-ritonavir study when maraviroc was coadministered with darunavir-ritonavir is therefore consistent with the interactions observed with other HIV PIs.…”

“…Therefore, since many antiretrovirals are potent inhibitors and/or inducers of these enzymes/transporters, pharmacokinetic interactions with maraviroc can be anticipated (4,6).…”

“…Concentrations of maraviroc, etravirine, darunavir, and ritonavir in plasma and concentrations of maraviroc in urine were determined using validated liquid chromatography with tandem mass spectrometry methods (4,20). Maraviroc in plasma and urine was assayed by Tandem Laboratories (West Trenton, NJ) under the supervision of Pfizer.…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…On the other hand, MVC is substrate of CYP3A4 and P-gp, hence, dose adjustment is frequently required when coadministered with drugs that alter its pharmacokinetics [118,119]. More recently, MVC has been identified as substrate of the transport protein OATP1B1 and the polymorphism 521T>C seems to be associated with higher MVC plasma levels [119].…”

Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

“…Since the majority of PIs are inhibitors of CYP3A and P-gp, potential exists for drug interactions with MVC. Indeed, MVC exposures have been shown to be increased in the presence of atazanavir, ritonavir (RTV)-boosted atazanavir (atazanavir/r), saquinavir, saquinavir/r, darunavir/r, and lopinavir/r (6)(7)(8). An MVC dose adjustment from 300 mg twice daily (BID) to 150 mg BID is therefore recommended when MVC is administered in combination with selected PIs and boosted PIs, which are considered to be potent CYP3A inhibitors (1,2).…”