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  11th International Workshop on Clinical Pharmacology of HIV Therapy
Sorrento, Italy
April 7-9, 2010
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Extra CYP3A Inhibitor Has Modest Impact on Already-Boosted Elvitegravir
  11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Adding twice-daily ketoconazole (a potent CYP3A inhibitor) to elvitegravir plus ritonavir (another strong CYP3A inhibitor) raised elvitegravir levels only modestly in a study of 18 healthy volunteers [1]. The finding is important because, if both are approved, the integrase inhibitor elvitegravir will probably be coformulated with the Gilead booster GS-9350 (cobicistat), so some people could end up taking two CYP3A inhibitors with elvitegravir. For that reason, the FDA asked Gilead to "study the effect of additional CYP3A inhibition on boosted elvitegravir with a second strong inhibitor like ketoconazole."
Elvitegravir, Gilead's investigational integrase inhibitor, relies primarily on CYP3A4 for metabolism. As a result, CYP3A4 inhibitors boost elvitegravir concentrations. Ritonavir and cobicistat can raise elvitegravir levels 20-fold. When metabolism by CYP3A4 is blocked, elvitegravir can turn to UGT1A1 or UGTIA3.
The antifungal ketoconazole was the best known CYP3A inhibitor until development of ritonavir. Therapeutic doses range from 200 to 400 mg once daily, and 200 mg twice daily can be used to study CYP3A inhibition. In planning this study, Gilead learned that ketoconazole is also a UGT1A1 inhibitor. That complicated the trial design because elvitegravir can use UGT1A1 as a secondary metabolism pathway.
The trial plan called for 18 healthy volunteers to take 150/100 mg of elvitegravir/ritonavir once daily on study days 2 through 11, then to add 200 mg of ketoconazole twice daily on days 12 to 15. To determine whether ketoconazole boosted elvitegravir via inhibition of CYP3A4 or UGT1A1, the investigators also gave 5 mg of midazolam on days 1, 11, and 15 because midazolam is a standard probe of CYP3A4 inhibition.
The study group included 12 men and 6 women with an average age of 27 years (range 19 to 44) and an average weight of 77 kg (range 57 to 97). No one suffered grade 3 or 4 adverse events, and only one person had a grade 2 event--somnolence when taking elvitegravir/ritonavir plus midazolam.
Adding ketoconazole to elvitegravir/ritonavir moderately increased elvitegravir's maximum concentration (Cmax), area under the curve (AUC), and trough, as indicated by the following geometric mean ratios (GMR) and 90% confidence intervals (CI) for elvitegravir/ritonavir versus elvitegravir/ritonavir/ketoconazole:
· Cmax: GMR 117%, 90% CI 104 to 133
· AUC: GMR 148%, 90% CI 136 to 162
· Trough: GMR 167%, 90% CI 148 to 188
Comparing midazolam levels when given with elvitegravir/ritonavir versus elvitegravir/ritonavir plus ketoconazole indicated that adding ketoconazole to elvitegravir/ritonavir resulted in only a 1% to 1.5% additional inhibition of CYP3A. Thus ketoconazole must be exerting most of its effect on elvitegravir via UGT1A1 inhibition. Compared with historical controls taking ketoconazole without another CYP3A inhibitor, ketoconazole levels in this study were higher, as they have been in earlier studies of ketoconazole taken with a ritonavir-boosted protease inhibitor.
Brian Kearney and Gilead colleagues concluded that giving already-boosted elvitegravir with a potent CYP3A and UGT1A1 inhibitor modestly raises elvitegravir exposure about 50%. They proposed that "clinically significant interactions via CYP3A or UGT interactions are not anticipated with boosted elvitegravir." The Gilead team recommended no dose reduction of boosted elvitegravir when given with ketoconazole and suggested a 200-mg maximum daily dose of ketoconazole with boosted elvitegravir.
1. German P, Mathias A, West S, Chuck S, Kearney BP. Evaluation of ritonavir-boosted Elvitegravir PK upon coadministration with a second potent CYP3A inhibitor, ketoconazole. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 48.