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Etravirine Lowers Cobicistat Exposure and Darunavir Trough
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18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Taking the nonnucleoside etravirine with fixed-dose darunavir/cobicistat lowered cobicistat exposure and more than halved the 24-hour concentration of darunavir [1]. Barcelona researchers suggested boosting darunavir with ritonavir when giving the protease inhibitor with etravirine.
With interest in coadministered darunavir/cobicistat plus etravirine growing, researchers at the Hospital Universitari Germans Trias i Pujol and other Barcelona centers conducted this open-label phase 1 trial to determine the impact of these agents on the pharmacokinetics and safety of the others. The trial involved 15 people taking darunavir/cobicistat (800/150 mg once daily) and 15 taking etravirine (400 mg once daily). The darunavir group added 400 mg of etravirine daily for 14 days, and the etravirine group added 800/150 mg of darunavir/cobicistat daily for 7 days. The investigators measured levels of the three agents on days 0 and 14 in the darunavir group and on days 0 and 7 in the etravirine group. Using linear mixed-effects models, they calculated geometric mean ratios (GMRs) from log-transformed 0-24 hour area under the concentration-time curve (AUC0-24), maximum concentration (Cmax), and trough concentration (C24).
Median age was 45.2 in the darunavir cohort and 50.0 in the etravirine cohort. Most study participants were men, and median weight stood around 24 kg/m(2). Most adverse events were minor or moderate. There were no serious adverse events, and no one stopped a drug after adding darunavir/cobicistat or darunavir. Everyone maintained an undetectable viral load throughout the study.
Darunavir/cobicistat had no impact on concentrations of etravirine, but etravirine had substantial impacts on both cobicistat and darunavir. When participants added etravirine to their darunavir/cobicistat regimen, cobicistat AUC0-24 fell 30% (GMR 0.70, 90% confidence interval [CI] 0.56 to 0.87), Cmax dropped 14% (GMR 0.86, 90% CI 0.75 to 0.98), and trough dropped 66% (GMR 0.34, 90% CI 0.23 to 0.50). Etravirine had little impact on darunavir AUC0-24 or Cmax but cut darunavir trough 56% (GMR 0.44, 90% CI 0.33 to 0.58)
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Based on these findings, the researchers proposed, "boosting darunavir with ritonavir instead of with cobicistat may be preferred if dual therapy with darunavir plus etravirine is to be used in clinical practice."
Reference
1. Molto J, Curran A, Valle M, et al. Pharmacokinetics of darunavir/cobicistat and etravirine alone and coadministered in HIV-infected patients. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_03.
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