Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV

AIDS. 2018 Mar 27;32(6):729-737. doi: 10.1097/QAD.0000000000001755.

Abstract

Objective: To evaluate dolutegravir pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.

Design: Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants.

Methods: Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum. Maternal delivery and postnatal infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005 μg/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons.

Results: Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (postpartum) women. Median dolutegravir AUC0-24,Cmax and C24 were 25-51% lower in the 2T and 3T compared with postpartum. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was less than 50 copies/ml for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir.

Conclusion: Dolutegravir exposure is lower in pregnancy compared with postpartum in the same women on once-daily dosing. Median AUC0-24 during pregnancy was similar to, whereas trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064 μg/ml). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls.

Publication types

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

MeSH terms

  • Adult
  • Chromatography, Liquid
  • Female
  • HIV / isolation & purification
  • HIV Infections / drug therapy*
  • HIV Integrase Inhibitors / administration & dosage
  • HIV Integrase Inhibitors / pharmacokinetics*
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Humans
  • Infant, Newborn
  • Male
  • Plasma / chemistry
  • Postpartum Period*
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy*
  • Prospective Studies
  • Tandem Mass Spectrometry
  • Viral Load
  • Young Adult

Substances

  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • dolutegravir