Reduced exposure to darunavir and cobicistat in HIV-1-infected pregnant women receiving a darunavir/cobicistat-based regimen

HIV Med. 2019 May;20(5):337-343. doi: 10.1111/hiv.12721. Epub 2019 Mar 14.

Abstract

Objectives: The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection.

Methods: This phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC24 h ), maximum plasma concentration (Cmax ) and minimum plasma concentration (Cmin )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated.

Results: Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC24 h , 50-56% lower; Cmax , 37-49% lower; Cmin , 89-92% lower); unbound darunavir exposure was also reduced (AUC24 h , 40-45% lower; Cmax , 32-41% lower; Cmin , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC24 h , 49-63% lower; Cmax , 27-50% lower; Cmin , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants.

Conclusions: In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.

Keywords: HIV; cobicistat; darunavir; pharmacokinetics; pregnancy.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cobicistat / administration & dosage
  • Cobicistat / pharmacokinetics*
  • Darunavir / administration & dosage
  • Darunavir / pharmacokinetics*
  • Drug Therapy, Combination
  • Female
  • Gestational Age
  • HIV Infections / drug therapy*
  • Humans
  • Infant, Newborn
  • Infectious Disease Transmission, Vertical / statistics & numerical data
  • Maternal Age
  • Postpartum Period / blood
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy*
  • Pregnancy Trimester, Second / blood
  • Treatment Outcome

Substances

  • Cobicistat
  • Darunavir