Infant Exposure to Dolutegravir Through Placental and Breast Milk Transfer: A Population Pharmacokinetic Analysis of DolPHIN-1

Abstract

Background: Rapid reduction in human immunodeficiency virus (HIV) load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, umbilical cord, breast milk, and infant plasma samples from DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation).

Methods: Pregnant women from Uganda and South Africa were randomized (1:1) to daily dolutegravir (50 mg/d) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks after delivery, with matched maternal and cord samples at delivery. Mothers were switched to efavirenz, and maternal and infant plasma and breast milk samples were obtained 24, 48, or 72 hours after the switch. Nonlinear mixed-effects modeling was used to describe dolutegravir in all matrices and to evaluate covariates.

Results: A total of 28 women and 22 infants were included. Maternal dolutegravir was described by a 2-compartment model linked to a fetal and breast milk compartment. Cord and breast milk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breast milk-to-infant and infant elimination rate constants. No covariate effects were observed. The median predicted infant dolutegravir half-life and median time to protein-adjusted 90% inhibitory concentration (0.064 mg/L) for those above this threshold were 37.9 (range, 22.1-63.5) hours and 108.9 (18.6-129.6) hours (4.5 [0.8-5.4] days) (n = 13), respectively.

Conclusions: Breastfeeding contributed relatively little to infant plasma exposure, but a median of 4.5 days of additional prophylaxis to some of the breastfed infants was observed after cessation of maternal dolutegravir (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.

Keywords: breast milk; dolutegravir; infant pharmacokinetics; population pharmacokinetics; pregnancy.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Dolutegravir visual predictive check for maternal plasma at third trimester (n = 28) (A), maternal plasma at delivery (n = 18) (B), maternal plasma postpartum (n = 27) (C), umbilical cord (n = 16) (D), and breast milk (n = 27) (E), along with the proportion below the lower limit of quantification (LLQ). Maternal plasma postpartum and breast milk samples were obtained after the final maternal dolutegravir dose. Lines represent percentiles of the observed data (fifth, 50th, and 95th percentiles), and shaded areas, 95% confidence intervals of the simulated data. Observed concentration-time data for maternal plasma (250 concentrations for the third trimester, 18 at delivery, and 265 postpartum), umbilical cord (16 concentrations), and breast milk (80 concentrations) are superimposed (open circles).

Figure 2.

Dolutegravir prediction-corrected visual predictive check for infant plasma (n = 22) after the final maternal dolutegravir dose, given a median of 7 days postpartum. Lines represent percentiles of the observed data (fifth, 50th, and 95th percentiles), and shaded areas, 95% confidence intervals of the simulated data. Observed concentration time data are superimposed (65 concentrations [open circles]).

Figure 3.

Schematic of the population pharmacokinetic model to simultaneously describe dolutegravir in maternal plasma, umbilical cord, and breast milk. Maternal plasma, cord and breast milk individual model estimates were then fixed to describe dolutegravir pharmacokinetics in infant plasma using a sequential approach. Abbreviations: CL/F, apparent oral clearance; ka, absorption rate constant; kBM-INF, breast milk–to–infant transfer rate constant; kBM-M, breast milk–to–mother transfer rate constant; kF-M, fetus-to-mother transfer rate constant; kINF, infant elimination rate constant; kM-BM, mother–to–breast milk transfer rate constant; kM-F, mother-to-fetus transfer rate constant; Q/F, intercompartmental clearance; RSE, relative standard error; VBM, volume of the breast milk compartment; Vc/F, apparent volume of distribution of the central compartment; VINF/F, infant apparent volume of distribution; Vp/F, volume of the peripheral compartment.