Maraviroc versus Darunavir
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Study Design
The design of this study was a phase I, open-label, placebo-controlled, randomized two period crossover study in healthy subjects to assess the effect darunavir/ritonavir has on the CCR5 antagonist maraviroc when the two are used in combination. (n=12) healthy men and women aged 21-55 were enrolled in a two-way cross over study to investigate the influence of darunavir/ritonavir on the plasma pharmacokinetics of maraviroc. Subjects received 150mg of maraviroc BID while subsequently receiving either a placebo or darunavir/ritonavir 600/100mg BID for days 1-9 and a single morning dose on day 10. There was a screening period of 28 days, two 10 day treatment periods with a minimum washout period of 14 days and a follow up visit 7-10 days after the last dose of the study drug. Maraviroc was administered under fasting conditions and darunavir/ritonavir was given with a standardized breakfast 1.5h after maraviroc dosing, on day 10. Serial blood samples were collected on days 1 to 9 predose and at 1, 2, 3, 4, 6, 8 and 12 hours post maraviroc dose on day 10. On days 8 and 10 darunavir/ritonavir concentrations were analyzed. Urine sampling was collected 0-12h post maraviroc dosing on day. Geometric least squares ratios and 90% confidence intervals were estimated.
Study Results
Based on GMRs and 90% confidence intervals, when compared with maraviroc + placebo there was a 4.05% increase in AUC12 (2.94, 5.59) and a 2.29% increase in Cmax (1.46, 3.59) of maraviroc upon co-administration with the boosted protease inhibitor darunavir.
This combination was generally well tolerated, with no serious adverse events. One volunteer discontinued treatment due to a rash.
Study Conclusions
Per the authors, clinically significant alterations in maraviroc exposure can be attributed to the co-administration with HIV protease inhibitors (or other modulaters of CYP3A4 activity). However dosage adjustments can compensate for the PK alterations
References
Kakuda TN. Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials. Antimicrobial Agents And Chemotherapy . 2016; 5: 2290-2296.
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