Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives

David W. Haas, Yoninah S. Cramer, Catherine Godfrey, Susan L. Rosenkranz, Francesca Aweeka, Baiba Berzins, Robert Coombs, Kristine Coughlin, Laura E. Moran, David Gingrich, Carmen D. Zorrilla, Paxton Baker, Susan E. Cohn, Kimberly K. Scarsi

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Objective In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. Methods In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. Results The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10-3), decreased plasma concentrations of etonogestrel (P = 1.7 × 10-3), and decreased ethinyl estradiol (P = 6.7 × 10-4). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. Conclusion CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Original languageEnglish (US)
Pages (from-to)45-53
Number of pages9
JournalPharmacogenetics and Genomics
DOIs
StateAccepted/In press - 2020

Keywords

  • HIV therapy
  • atazanavir
  • drug interaction
  • efavirenz
  • ethinyl estradiol
  • etonogestrel
  • hormonal contraceptives
  • pharmacogenetics
  • pharmacokinetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Haas, D. W., Cramer, Y. S., Godfrey, C., Rosenkranz, S. L., Aweeka, F., Berzins, B., Coombs, R., Coughlin, K., Moran, L. E., Gingrich, D., Zorrilla, C. D., Baker, P., Cohn, S. E., & Scarsi, K. K. (Accepted/In press). Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives. Pharmacogenetics and Genomics, 45-53. https://doi.org/10.1097/FPC.0000000000000396