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

Abstract

Background Rapid reduction of HIV viral load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, cord, breastmilk and infant plasma of DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation). Methods Pregnant women from Uganda and South Africa were randomised (1:1) to daily dolutegravir (50 mg) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks of delivery, with matched maternal and cord samples at delivery. Mothers switched to efavirenz and maternal and infant plasma and breastmilk samples taken 24, 48 or 72 hours post-switch. Nonlinear mixed effects (NONMEM v. 7.4) was used to describe dolutegravir in all matrices and to evaluate covariates. Results Twenty-eight women and 22 infants were included. Maternal dolutegravir was described by a two-compartment model linked to a fetal and breastmilk compartment. Cord and breastmilk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breastmilk-to-infant and infant elimination rate constants. No covariate effects were observed. Predicted infant dolutegravir half-life and time to protein adjusted-IC90 (0.064 mg/L) for those above this threshold were 37.9 hours (22.1-63.5) and 108.9 hours [(18.6-129.6); 4.5 days (0.8-5.4); n=13]. Conclusions Breastfeeding contributed relatively little to infant plasma exposures but a median of 4.5 days additional prophylaxis to some of the breastfed infants was observed following maternal dolutegravir cessation (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.

Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study

“…The infant concentrations of other ARVs were consistent with previous data showing differential exposure with very low or undetectable levels for lamivudine, 4 , 23 emtricitabine, tenofovir derived from tenofovir disoproxil fumarate 25 and raltegravir, 29 whereas efavirenz, nevirapine and dolutegravir were shown to be detectable in infants. 4 , 30 , 31 We observed that dolutegravir levels in the infant are comparable or higher than levels measured in the breastmilk, as also reported previously. 30 , 31 This observation relates to the fact that dolutegravir is mainly metabolized by UGT1A1, a drug-metabolizing enzyme whose immaturity, particularly in preterm infants, can result in slow elimination of the drug.…”

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

“…DTG levels were measured in maternal plasma during prenatal and postnatal period, up to postnatal day (PND) 21. As DTG is known to transfer to infants through milk in addition to transplacental transfer [40][41][42], maternal plasma drug levels were measured up to the day of weaning of pups (PND 21). At GD 8.5 and 16.5, high DTG concentrations were detected in plasma of dams, 38,628.63 ± 4855.53 and 27,296.3 ± 2701.15 ng/ mL, respectively (Fig.…”

Optimizing Dolutegravir Initiation in Neonates Using Population Pharmacokinetic Modeling and Simulation

“…popPK parameter estimates of DTG were in agreement with values reported in the literature. [12][13][14] In DTGnaïve infants, a 5-mg DTG dose at birth with a second dose after 48 hours maintained median concentrations above the lower bound of the target range (0.77 mg/mL) and below the upper bound of the target range (7.34 mg/mL representing 2fold above the adult Cmax value). In DTG-exposed infants, a 5-mg DTG dose at 24 hours after birth with a second dose after 48 hours maintained median concentrations within or nearly within the target range, even if the last maternal DTG dose was taken as soon as 6 hours or as long as 24 hours before delivery.…”

“…Based on limited data, DTG is detectable in small amounts of breast milk but not likely to contribute significantly to DTG plasma concentrations in the neonate, whereas breastfeeding infants have higher plasma bilirubin concentrations. 13,22 However, acquisition of DTG through breast milk was not considered in this analysis. Finally, a limited range of maternal and neonatal dosing scenarios was explored.…”