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Dolutegravir Levels Similar in Third Trimester and After Delivery
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18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Dolutegravir exposure during the third trimester of pregnancy was similar to postpartum levels in a small European study [1]. Women always maintained a dolutegravir level above the 90% inhibitory concentration at the end of the dosing interval.
Physiologic changes during pregnancy affect drug concentrations, usually yielding lower exposure. Because little is known about levels of the HIV integrase inhibitor dolutegravir during pregnancy, researchers working with the European PANNA network [2] conducted this study.
For this open-label multicenter trial, the PANNA team recruited pregnant women taking 50 mg of dolutegravir once daily. Participants had intensive steady-state 24-hour pharmacokinetic profiling during the third trimester (around 33 weeks gestation) and 4 to 6 weeks after delivery. Cord blood and matching maternal blood samples were assessed when possible.
The study group included 9 women, 3 of whom had only third-trimester sampling and 1 of whom was excluded from the pharmacokinetic analysis. Median age stood at 30 years (range 21 to 42), gestational age at 38 weeks (range 34 to 40), and birth weight at 3180 g (range 2120 to 3530). All women had a plasma load below 50 copies when approaching pregnancy.
Comparison of third trimester and postpartum dolutegravir levels showed similar 24-hour area under the concentration-time curve (geometric mean ratio [GMR] 0.95, 95% confidence interval [CI] 0.60 to 1.48), maximum concentration (GMR 1.07, 95% CI 0.78 to 1.47), and clearance (CL/F) (GMR 1.06, 95% CI 0.67 to 1.66). Dolutegravir trough concentration was modestly lower in the third trimester than after delivery (GMR 0.66, 95% CI 0.32 to 1.36), as was terminal half-life (GMR 0.75, 95% CI 0.58 to 0.98). In 5 mother-infant pairs, median cord blood/maternal ratio for dolutegravir was 1.4 (range 0.35 to 1.6).
Seven of 8 children did not acquire HIV infection, while the status of the eighth child remained unknown at the time of this presentation. There was 1 intrauterine fetal death at 34 weeks of pregnancy attributed to cholestasis pregnancy syndrome. Two serious adverse events arose, but neither was drug-related.
The PANNA researchers concluded that dolutegravir exposure and trough levels appear to be similar in the third trimester and after delivery. That finding contrasts with the usually lower third-trimester values for other antiretrovirals, including darunavir, atazanavir, tenofovir, emtricitabine, and rilpivirine. Because dolutegravir efficiently crosses the placenta, the investigators suggested the integrase inhibitor "may have potential for pre-exposure prophylaxis." They added that their findings should be confirmed in a larger group of women.
References
1. Bollen P, Colbers A, Schalkwijk S, et al. A comparison of the pharmacokinetics of dolutegravir during pregnancy and postpartum. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_07.
2. PANNA Network. http://www.pannastudy.com/network
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