850: Evaluation of breast milk concentrations following brexanolone iv administration to healthy lactating women

Abstract

Brexanolone iv, a proprietary, intravenous formulation of allopregnanolone, is an investigational positive allosteric modulator of GABAA receptors and is under FDA review for the treatment of postpartum depression. The brexanolone iv dose regimen yields plasma concentrations of allopregnanolone that approximate endogenous levels at the end of pregnancy. We evaluated concentrations of allopregnanolone in breast milk and plasma for 7 days after the start of brexanolone iv infusion. This open-label, Phase 1b trial enrolled 12 healthy, lactating women, who were ≤6 months postpartum. Subjects received a 60-hour brexanolone iv infusion, titrated to a maximum of 90 μg/kg/h, as inpatients and were followed through Day 7. Breast milk was collected ad libitum at least every 12 hours through Day 7. Milk samples were retained for analysis. Expressed milk was not given to infants during the study. Plasma and breast milk were analyzed for allopregnanolone concentrations. Brexanolone iv safety and tolerability were monitored throughout the study. Plasma concentrations of allopregnanolone increased during dose titration and declined during dose taper, with an average steady state concentration (Cavg) of 70.56 ng/mL (95% CI 61.8-80.4), a t1/2 of 11.3 hours (95% CI 9.8- 13.1), and an area under the curve to infinity (AUC∞) of 3736.5 ng·h/mL (95% CI 3309.1-4219.1). Breast milk concentrations of allopregnanolone followed a similar pattern and fell below the limit of detection (5 ng/mL) in the majority of the women by approximately 3 days after infusion cessation. Overall pharmacokinetics results showed a rapid equilibrium between milk and plasma. The milk to plasma ratio appeared to be constant over a large range of plasma concentrations, with varying volumes of milk expressed and across subjects. There were no deaths, serious or severe adverse events, or clinically significant changes in safety tests, including laboratory results. Allopregnanolone concentrations were detected in breast milk of women receiving brexanolone iv. Concentrations in milk followed plasma concentrations closely, with rapid decline after the end of the 60-hour infusion to undetectable levels 3 days after the end of the infusion. There was no apparent accumulation of allopregnanolone in plasma or breast milk.