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Impact of Stomach Acid Reducers on Cobicistat and Elvitegravir
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Doses of elvitegravir and cobicistat (the experimental integrase inhibitor and booster) will not have to change when taken with a proton pump inhibitor, according to results of two studies in healthy volunteers [1]. The same studies indicate that elvitegravir/cobicistat will have to be taken simultaneously with and/or 12 hours after H2-receptor antagonists.
Along with tenofovir/emtricitabine, cobicistat-boosted elvitegravir is coformulated as a single once-daily pill (QUAD) and is in phase 3 trials for antiretroviral-naive people. Cobicistat solubility is significantly higher in acidic conditions than in neutral conditions. As a result, it is important to understand the impact of acid-reducing agents on cobicistat levels, because lower cobicistat concentrations may not boost elvitegravir (or protease inhibitors) to therapeutic levels.
Gilead Sciences researchers assessed cobicistat and elvitegravir levels in healthy volunteers when these agents are taken alone or with the H2-receptor antagonist famotidine or the proton pump inhibitor omeprazole. In all the interaction studies, the famotidine dose was 40 mg once daily, the omeprazole dose 20 mg once daily, and the elvitegravir/cobicistat dose 150/150 mg once daily, as in the QUAD tablet.
Study 1 involved 33 volunteers in three sequences: elvitegravir/cobicistat alone for 8 days followed by 8 days of (1) elvitegravir/cobicistat plus famotidine 12 hours later, (2) elvitegravir/cobicistat plus omeprazole 2 hours earlier, and (3) elvitegravir/cobicistat plus omeprazole 12 hours later. Study 2 had 16 volunteers in a 2 x 2 crossover design: (1) elvitegravir/cobicistat alone for 8 days, then simultaneous elvitegravir/cobicistat and famotidine for 8 days, and (2) simultaneous elvitegravir/cobicistat and famotidine for 8 days, then elvitegravir/cobicistat alone for 8 days.
The study plan said elvitegravir and cobicistat exposure would be considered not reduced if the lower bound the 90% confidence interval of the geometric mean ratios of elvitegravir/cobicistat plus an acid reducer versus elvitegravir/cobicistat alone were greater than 0.7 for the elvitegravir and cobicistat area under the concentration-time curve (AUC) and maximum concentration (Cmax). The researchers also evaluated elvitegravir and cobicistat trough concentration (Ctau).
Study 1 included 18 men and 15 women with an average age of 34 and an average weight of 70.8 kg. Twenty-five volunteers (76%) were white. The study 2 group was evenly divided between men and women. Their ages and weights averaged 33 and 74.2 kg, and 10 (63%) were white. One of 33 people dropped out of study 1 when she became pregnant; all 16 volunteers completed the second study.
There were no serious adverse events in either study and no grade 3 or 4 adverse events or treatment-related lab abnormalities. Grade 1 dyspepsia was the only drug-related problem in study 1. Headache was the most frequent complaint in study 2, with only one case rated grade 2.
Both elvitegravir and cobicistat met the predefined criterion indicating lack of interaction with either famotidine or omeprazole, as indicated by the geometric mean ratios and (in parentheses) the lower bound of the 90% confidence interval (CI) for each of the interaction tests:
Elvitegravir geometric mean ratio (and lower bound of 90% CI) for elvitegravir/cobicistat plus acid reducer versus elvitegravir/cobicistat alone:
With famotidine 12 hours later: AUC 103% (94.9), Cmax 102% (89.4), Ctau 118% (105)
With simultaneous famotidine: AUC 103% (98.1), Cmax 100% (91.7), Ctau 107% (98.5)
With omeprazole 2 hours earlier: AUC 110% (102), Cmax 116% (104), Ctau 113% (95.5)
With omeprazole 12 hours later: AUC 105% (92.9), Cmax 103% (91.9), Ctau 110% (91.9)
Cobicistat geometric mean ratio (and lower bound of 90% CI) for elvitegravir/cobicistat plus acid reducer versus elvitegravir/cobicistat alone:
With famotidine 12 hours later: AUC 105% (102), Cmax 104% (99.1), Ctau 115% (106)
With simultaneous famotidine: AUC 103% (96.8), Cmax 106% (99.4%), Ctau 111% (99.8)
With omeprazole 2 hours earlier: AUC 92.4% (84.8), Cmax 90.2% (81.8), Ctau 92.8% (73.6)
With omeprazole 12 hours later: AUC 98.7% (89.0), Cmax 94.4% (85.1), Ctau 102% (81.6)
The Gilead investigators concluded that no dosing restrictions are necessary when elvitegravir plus cobicistat are taken with proton pump inhibitors. They believe data so far indicate that elvitegravir and cobicistat should be administered simultaneously with and/or 12 hours after dosing of H2-receptor antagonists.
Reference
1. Mathias A, Koziara J, Wei L, Warren D, Kearney BP. Effect of acid reducing agents on the relative bioavailability and pharmacokinetics of cobicistat-boosted elvitegravir. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract P_13.
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