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  18th International Workshop on
Clinical Pharmacology of Antiviral Therapy
June 14-17, 2017
Chicago, Ill.C
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COBI-PI Regimens Raise Drospirenone Levels in Oral Contraceptive
  18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Cobicistat (COBI)-boosted atazanavir or darunavir raised levels of drospirenone in the oral contraceptive drospirenone/ethinyl estradiol (DRSP/EE, Yaz) [1]. Darunavir/cobicistat modestly lowered EE levels in the contraceptive.
Interactions between antiretrovirals, their boosters, and hormonal oral contraceptives are expected because of overlapping use of the same metabolizing pathways, some of which certain agents inhibit. Cobicistat inhibits CYP3A enzymes, and hormonal contraceptives are extensively metabolized by CYP3A, CYP2C9/19, UGT, and SULT. Gilead Sciences investigators conducted this study to assess the impact of COBI (boosting atazanavir or darunavir) on the pharmacokinetics of drospirenone/ethinyl estradiol (DRSP/EE, Yaz).
The study involved two cohorts, each including 18 healthy women. Participants took a single dose of DRSP/EE (3 mg/20 ug) followed by a no-drug washout period. Then they began daily doses of atazanavir/COBI (300/150 mg) or darunavir/cobicistat (800/150 mg) with a single dose of DRSP/EE added on day 14 to atazanavir/COBI and on day 16 to darunavir/COBI. The researchers used geometric least-squares mean ratios (GMR) and 90% confidence intervals (CI) to compare pharmacokinetic parameters of DRSP and EE alone versus with the COBI-boosted protease inhibitor (PI). They set the no-effect bounds at a 90% CI of 70% to 143%.
Fourteen of 18 women completed treatment with atazanavir/cobicistat, as did 15 of 18 with darunavir/cobicistat. Drug-related grade 1 maculopapular rash--a known side effect of boosted PIs--explained all 7 discontinuations. There were no grade 3 or 4 adverse events. Median age was 30 in the atazanavir group and 28 in the darunavir group, and both groups had a median body mass index of 26 kg/m(2).
Atazanavir/COBI did not affect exposure of EE but increased DRSP exposure (GMR% 230 for area under the concentration-time curve (AUC) and 112 for maximum concentration (Cmax). The heightened DRSP exposure probably reflects COBI inhibition of CYP3A, the researchers noted.
Darunavir/COBI slightly lowered exposure of EE (GMR% 70 for AUC and 86 for Cmax), while boosting exposure of DRSP (GMR% 158 for AUC and 115 for Cmax). The researchers suggested the lower EE exposure with darunavir/COBI may be attributed to induction of P-gp or CYP2C9.
The Gilead investigators observed that Yaz (DRSP/EE) prescribing information [2] recommends close monitoring when giving the oral contraceptive with a strong CYP3A inhibitor because of potential hyperkalemia (high potassium). The researchers concluded that this recommendation should apply to COBI boosting.
1. Majeed S, West S, Jiang S, et al. Confirmation of the drug-drug interaction (DDI) potential between cobicistat-boosted antiretroviral regimens and hormonal contraceptives. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_05.
2. Yaz prescribing and safety information. http://www.yaz-us.com/