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Darunavir Boosting with GS-9350 (Cobicistat)
or Ritonavir in Healthy Volunteers
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
GS-9350, the antiretroviral-boosting agent being developed by Gilead Sciences and now called cobicistat, appeared to lift darunavir levels adequately in 31 healthy volunteers, although the study left open questions about a lower darunavir trough with cobicistat than with ritonavir [1].
Earlier work showed that cobicistat raises levels of drugs metabolized by the CYP3A enzyme, including midazolam [2], the integrase inhibitor elvitegravir, and the protease inhibitor atazanavir. This study compared cobicistat with ritonavir in 33 healthy volunteers who took the boosters with darunavir. Gilead investigators randomized volunteers to take darunavir/cobicistat (800/150 mg once daily) or darunavir/ritonavir (800/100 mg once daily) for 10 days. After 4 days taking neither drug, study participants switched to the other regimen. Investigators observed all doses, which were taken after a 400-kcal meal including 13 g of fat.
The Gilead team compared the two regimens by figuring the geometric mean ratio of darunavir/cobicistat to darunavir/ritonavir. Before the study began, they decided that 90% confidence interval [CI] bounds of 80% to 125% for darunavir maximum concentration (Cmax), trough concentration, and area under the curve (AUC) would indicate equivalence.
All but 2 of the 33 study participants were men. Eighteen people (54.5%) were white, 11 black, and 4 Asian or Hispanic. Their age averaged 27 years (range 20 to 45) and their weight 74.9 kg (range 52.2 to 90.7).
Two people dropped out before completing the study, one because of a treatment-related rash and the other because of failure to keep study appointments. Eleven people had treatment-emergent adverse events while taking cobicistat and 13 while taking ritonavir. Two people complained of headache while taking cobicistat and 4 while taking ritonavir. Two people had maculopapular rash while taking cobicistat and 2 while taking ritonavir. There were no grade 3 or 4 side effects or lab abnormalities.
Among the 31 people who completed the study, geometric mean ratio of darunavir/cobicistat versus darunavir/ritonavir was equivalent for AUC (102%, 90% CI 97.4 to 106) and Cmax (103%, 90% CI 100 to 106).
Darunavir troughs were about 30% lower with cobicistat than with ritonavir, at a geometric mean ratio of 69.4% (90% CI 59.0 to 81.7). According to study criteria, that meant darunavir boosting by cobicistat is not equivalent to boosting with ritonavir. The Gilead investigators attributed that difference to an unexpected upswing in darunavir concentration from hour 20 to hour 24 with darunavir/ritonavir. When the researchers looked at predose darunavir concentrations after multiple doses, they found equivalent levels with ritonavir and cobicistat (geometric mean ratio 89.4%, 90% CI 80.4 to 99.4).
When boosted by cobicistat, darunavir trough concentrations remained more than 18 times above the protein-binding-adjusted 50% effective concentration (EC50) for wild-type (nonresistant) virus (55 ng/mL). Predose darunavir levels were more than 37 times above the EC50 for wild-type virus.
References
1. Mathias A, Liu HC, Warren D, Sekar V, Kearney BP. Relative bioavailability and pharmacokinetics of darunavir when boosted with the pharmacoenhancer GS-9350 versus ritonavir. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 28.
2. Mathias AA, German P, Murray BP, et al. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 2010;87:322-329.
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