Allopregnanolone Concentrations in Breast Milk and Plasma from Healthy Volunteers Receiving Brexanolone Injection, With Population Pharmacokinetic Modeling of Potential Relative Infant Dose

BACKGROUND AND OBJECTIVE: Women with postpartum depression (PPD) may expose their infants to antidepressants via breast milk. Brexanolone is the only FDA-approved antidepressant specifically indicated for the treatment of PPD. This open-label, phase Ib study of healthy lactating volunteers assessed pharmacokinetic (PK) properties of brexanolone and a population PK (PopPK) model determined the relative infant dose (RID) in breastfeeding mothers. METHODS: Twelve participants received a 60-h infusion of brexanolone (titration up to 90 µg/kg/h). Allopregnanolone concentration was measured in breast milk and plasma. The RID was computed using a nonlinear mixed-effects PopPK model of patients with PPD and healthy women (N = 156). Model results were extended across an integrated dataset of participants through day 7. RESULTS: Allopregnanolone concentration–time profiles were similar between breast milk and plasma (partition coefficient for concentration gradient [milk : plasma] 1.36). Mean (95% CI) C(max) was 89.7 ng/mL (74.19–108.39), and median (95% CI) t(max) was 47.8 h (47.8–55.8) in plasma. The overall PK profile was best described by a two-compartment model with linear elimination and distribution. Body weight was the only significant covariate identified. There were no apparent differences in PopPK AUC and C(max) between participants with or without concomitant antidepressant treatment. Maximum RID was 1.3%. CONCLUSION: The PopPK model successfully described the variability and concentration–time profiles of allopregnanolone in breast milk and plasma in healthy participants and in the plasma of brexanolone-treated patients with PPD. The rapid elimination of allopregnanolone from plasma and breast milk, and low RID, suggests the appropriateness of brexanolone weight-based dosing and supports other PK-related labeling recommendations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01155-w.