Dolutegravir (DTG), an integrase strand transfer inhibitor, is metabolized by UGT1A1 and CYP3A4. It has not been studied in pregnant women or infants. This study described DTG exposure during pregnancy compared to postpartum and in infant washout samples after delivery.
IMPAACT protocol P1026s is an ongoing, nonrandomized, open-label, parallel-group, multi-center phase-IV prospective study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women. Intensive steady-state 24 hour PK profiles of DTG 50 mg once-daily were performed during the 2nd trimester (2T), 3rd trimester (3T) and 6-12 weeks postpartum (PP). Infant DTG washout samples were collected if birth weight > 1000 grams and there were no severe malformations or medical conditions. Dolutegravir was measured by validated LC-MS/MS with a quantitation limit of 0.005 mcg/mL. A two-tailed Wilcoxon signed rank test (α = 0.10) was employed for paired within-subject comparison.
Thirteen subjects from the United States were enrolled – 9 black, 3 white, 1 American Indian / Alaskan Native with a median 3T age of 32 years (range 22 – 40). DTG PK data were available for 5, 11 and 4 women in 2T, 3T and PP. PK parameters are represented as median (interquartile range) in the table below. AUC0-24 and C24h appeared to be lower in the 3T compared to PP, while clearance appeared to be higher, but no significant differences for any PK parameters were found in paired comparisons between 3T and PP (n = 4). Washout DTG PK data were available for 5 infants; elimination half-life was 35 hours (range 32 – 55). Viral load at delivery was < 50 copies/mL for 13 of 13 women (100%). Median infant gestational age at birth was 38.9 weeks. Thirteen of 13 infants were HIV-negative based on best available data.
DTG exposure may be lower in pregnancy compared to postpartum. Infant elimination half-life was over twice that of maternal subjects and historical non-pregnant adult controls. More PK, safety and outcome data in pregnant women are needed before DTG can be recommended for clinical use during pregnancy.