Maraviroc versus Saquinavir
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Study Design
The design of this study was an open label, randomized, placebo-controlled study done in healthy subjects, to assess the effect of CYP3A4 inhibitor combinations on the pharmacokinetics of the CCR5 antagonist maraviroc. (n=32) healthy men and women aged 19-44 were enrolled in a four-treatment, four parallel-group study to investigate the influence of Saquinavir/ritonavir (SQV/r) on the plasma pharmacokinetics of maraviroc. In one treatment group, on days 1-7 subjects received 100mg of maraviroc BID alone while on days 8-21, maraviroc 100mg BID was administered with SQV/r 1000/100mg BID. On days 21-28 the maraviroc dose was adjusted based on predefined criteria and any interaction from days 7-21, in this case the dose given on those days was 25mg BID. The final doses of maraviroc were administered on day 28. During the duration of the study subjects received 28 total days of maraviroc and 21 days of SQV/r. Subjects were fasting 2 hours before and 1 hour after maraviroc dosing. SQV/r was dosed 1.5 hours after the morning maraviroc dose and were preceded by a meal. Serial blood samples were collected periodically during the 28 day period, and predose and post dose samples at intervals up to 12h post dose were collected on days 7, 21, and 28. Also predose and 2h and 4h postdose samples were collected on day 17 to allow for dose adjustment recommendations. Geometric least squares ratios and 90% confidence intervals were estimated.
Study Results
Based on GMRs and 90% confidence intervals, when comparing day 21 with day 7 of treatment there was a 832% increase in AUC (611, 1130) and a 423% increase in Cmax (260, 688) of maraviroc upon co-administration with the boosted protease inhibitor combination saquinavir/ritonavir.
This combination was generally well tolerated, with no adverse events leading to treatment discontinuation.
Study Conclusions
Per the authors, clinically significant alterations in maraviroc exposure can be attributed to the co-administration with HIV protease inhibitors (or other modulators of CYP3A4 activity). However dosage adjustments can compensate for the PK alterations
References
Abel S, Russell D, Taylor-Worth RJ, Ridgway CE, Muirhead GJ. Effects of cyp3a4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers. British Journal Of Clinical Pharmacology. 2008; S1: 27-37.
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