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Twice-Daily Cobicistat Effect Differs With Darunavir and Tipranavir
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Cobicistat taken twice daily at 150 mg with darunavir yielded darunavir concentrations equivalent to those attained with ritonavir twice daily in a study of HIV-negative volunteers [1]. And coadministration of the integrase inhibitor elvitegravir or the nonnucleoside etravirine did not affect darunavir exposure. But exposures of twice-daily cobicistat-boosted tipranavir were markedly lower than with twice-daily tipranavir/ritonavir.
Previous work found that once-daily cobicistat at 150 mg boosts elvitegravir and the protease inhibitors darunavir and atazanavir to levels similar to those attained with once-daily ritonavir at 100 mg. Because ritonavir is usually used twice daily and since cobicistat had not been studied as a twice-daily booster, Gilead investigators planned this three-cohort study in healthy volunteers.
In a fixed-sequence crossover design, volunteers took each study treatment for 10 days.
Cohort 1: 12 volunteers took cobicistat at a dose of 150 mg twice daily.
Cohort 2: 24 volunteers took darunavir/ritonavir at 600/100 mg twice daily, no drugs for 7 days, then darunavir/cobicistat at 600/150 mg twice daily. At that point two groups of 12 volunteers were randomly assigned to add elvitegravir at 150 mg daily or the nonnucleoside etravirine at 200 mg twice daily.
Cohort 3: 12 volunteers took tipranavir/ritonavir at 500/200 mg twice daily, no drugs for 7 days, then tipranavir/cobicistat at 500/150 mg twice daily.
Half of the volunteers were women and about one quarter were black. Age averaged around 33 and weight around 73 kg.
One of 12 people in cohort 1 withdrew consent during the study. No one dropped out of cohort 2, and adverse event incidence was lower with darunavir/cobicistat than with darunavir/ritonavir (4% versus 18%). One person dropped out of cohort 3 with a grade 2 rash while taking tipranavir/ritonavir. No one in any cohort had grade 3 or 4 adverse events, and no creatinine- or kidney-related lab abnormalities were recorded.
Cobicistat exposures were 2- to 4-fold higher with twice-daily dosing than with once-daily dosing in historical controls. Twice-daily cobicistat exposures were about 2-fold lower with darunavir than with cobicistat alone (12,200 versus 23,100 ng*h/mL) but well within the range of cobicistat levels that provide adequate boosting. Cobicistat area under the concentration-time curve (AUC) was 90% lower with tipranavir twice daily than with cobicistat twice daily alone (1620 versus 23,100 ng*h/mL). That finding reflects CYP3A induction by tipranavir.
Darunavir and elvitegravir trough concentrations were lower with darunavir plus elvitegravir/cobicistat than with darunavir/cobicistat or darunavir/ritonavir, with QUAD (the 4-in-1 pill containing elvitegravir, cobicistat, tenofovir, and emtricitabine), or with elvitegravir/ritonavir. Cobicistat twice-daily exposures were similar with darunavir/cobicistat plus elvitegravir and darunavir/cobicistat without elvitegravir.
Darunavir exposures were bioequivalent when given with twice-daily cobicistat and twice-daily ritonavir: mean 74,400 versus 67,900 ng*h/mL for AUC, 9040 versus 8390 ng/mL for maximum concentration (Cmax), and 3960 versus 3800 ng/mL for minimum concentration (Ctau).
Cobicistat-boosted darunavir exposures were not affected by coadministration of elvitegravir or etravirine. Etravirine mean trough with darunavir/cobicistat (384 ng/mL) was higher than with darunavir/ritonavir (268 ng/mL).
Across the board, tipranavir exposures were lower with twice-daily cobicistat boosting than twice-daily ritonavir boosting: Geometric mean ratios were 46.2 (90% confidence interval [CI]) 40.0 to 53.4) for tipranavir 12-hour AUC, 62.2 (90% CI 54.9 to 70.5) for Cmax, and 14.4 (90% CI 11.7 to 17.6) for Ctau.
Summing up, the Gilead investigators list the following conclusions:
-- Cobicistat at 150 mg twice daily provided about 4-fold higher cobicistat exposure than 150 mg once daily.
-- Darunavir exposures were bioequivalent with darunavir/cobicistat twice daily and darunavir/ritonavir twice daily.
-- Cobicistat-boosted darunavir exposure was unaffected by elvitegravir or etravirine.
-- Elvitegravir and etravirine exposures with darunavir/cobicistat were comparable to historical and reference values.
-- Tipranavir and cobicistat exposures were markedly lower with tipranavir/cobicistat than with tipranavir/ritonavir.
-- The long-term safety of twice-daily cobicistat remains to be determined.
Reference
1. Ramanathan S, Wang H, Custodio J, Hepner-Harris M, Cheng A, Kearney BP. Lack of clinically relevant drug interactions between GS-7340 and efavirenz. 13th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2012. Barcelona. Abstract P_08.
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