Confirmation of the Drug–drug Interaction Potential between Cobicistat-boosted Antiretroviral Regimens and Hormonal Contraceptives

Abstract

Background Cobicistat (COBI), a CYP3A inhibitor, is a pharmacokinetic enhancer that increases exposures of the HIV protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV). The potential drug interaction between COBI-boosted PIs and hormonal contraceptives, which are substrates of intestinal efflux transporters and extensively metabolized by CYP enzymes, glucuronidation and sulfation, was evaluated. Methods This was a Phase I, open-label, two cohort (n=18/cohort), fixed-sequence study in healthy females that evaluated the drug–drug interaction (DDI) between multiple-dose ATV+COBI or DRV+COBI and single-dose drospirenone/ethinyl estradiol (EE). DDIs were evaluated using 90% confidence intervals of the geometric least-squares mean ratios of the test (drospirenone/EE+boosted PI) versus reference (drospirenone/EE) using lack of DDI boundaries of 70–143%. Safety was assessed throughout the study. Results 29/36 participants completed the study. Relative to drospirenone/EE alone, drospirenone area under the plasma concentration versus time curve extrapolated to infinity (AUCinf) was 1.6-fold and 2.3-fold higher, and maximum observed plasma concentration (Cmax) was unaltered, upon coadministration with DRV+COBI and ATV+COBI, respectively. EE AUCinf decreased 30% with drospirenone/EE + DRV+COBI and was unchanged with ATV+COBI + drospirenone/EE, relative to drospirenone/EE alone. Study treatments were generally well tolerated. The majority of adverse events were mild and consistent with known safety profiles of the compounds. Conclusions Consistent with COBI-mediated CYP3A inhibition, drospirenone exposure increased following coadministration with COBI-containing regimens, with a greater increase with ATV+COBI. Thus, clinical monitoring for drospirenone-associated hyperkalaemia is recommended with DRV+COBI and ATV+COBI should not be used with drospirenone. Lower EE exposure with DRV+COBI may be attributed to inductive effects of DRV on CYP enzymes and/or intestinal efflux transporters (that is, P-gp) involved in EE disposition.

Potential risk of drug–drug interactions with hormonal contraceptives and antiretrovirals: prevalence in women living with HIV

“…In our cohort study, there were no WLH on concurrent HC and PIs boosted with cobicistat; this combination has been noted to present a potential issue, especially with drospirenone-associated hyperkalemia. 34 …”

Contraception and Abortion Care for People Living With HIV: A Clinical Guide for Reproductive Health Practitioners

“…56,57 For patients who are taking darunavir/ritonavir and on COCs, additional contraception may be required due to inadequate hormone levels. 58 Progestin levels may also be affected by ART medications: although a prospective study in 2019, which followed 15 women on ritonavir-boosted protease inhibitors, did not show any difference in ethinyl estradiol concentrations, the authors did find increased levels of levonorgestrel. 59 Likewise, an earlier prospective, nonrandomized trial suggested that norethisterone-based progestin-only contraceptives exhibit increased drug levels when co-administered with ritonavir-boosted protease inhibitors.…”

“…61 Another drug-drug interaction of clinical concern is hyperkalemia when drospirenone-containing contraceptives are used along with cobicistat-containing ART regimens. 58 Currently, drospirenone-containing contraceptives are generally contraindicated in users of cobicistat-boosted protease inhibitors when an alternative or additional contraceptive method is available. 19 In terms of the combined hormonal vaginal contraceptive rings, a study in 2019, including 84 women living with HIV, showed that efavirenz decreased etonogestrel levels by 79% and ethinyl estradiol levels by 59%, whereas ritonavir-boosted atazanavir (a protease inhibitor) increased etonogestrel levels by 71% and lowered ethinyl estradiol concentrations.…”

“…Pharmacokinetic changes such as decreased ethinyl estradiol levels have been previously observed in women living with HIV using COCs while on a nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor 56,57 . For patients who are taking darunavir/ritonavir and on COCs, additional contraception may be required due to inadequate hormone levels 58 . Progestin levels may also be affected by ART medications: although a prospective study in 2019, which followed 15 women on ritonavir‐boosted protease inhibitors, did not show any difference in ethinyl estradiol concentrations, the authors did find increased levels of levonorgestrel 59 .…”

“…Another drug–drug interaction of clinical concern is hyperkalemia when drospirenone‐containing contraceptives are used along with cobicistat‐containing ART regimens 58 . Currently, drospirenone‐containing contraceptives are generally contraindicated in users of cobicistat‐boosted protease inhibitors when an alternative or additional contraceptive method is available 19…”