Sage Therapeutics, Inc., 215 First Street, Cambridge, MA, 02142, USA.
qPharmetra, LLC, Cary, NC, USA.
Clin Pharmacokinet. 2022 Sep;61(9):1307-1319. doi: 10.1007/s40262-022-01155-w. Epub 2022 Jul 23.
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.
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.
Allopregnanolone concentration-time profiles were similar between breast milk and plasma (partition coefficient for concentration gradient [milk : plasma] 1.36). Mean (95% CI) C was 89.7 ng/mL (74.19-108.39), and median (95% CI) t 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 between participants with or without concomitant antidepressant treatment. Maximum RID was 1.3%.
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.
患有产后抑郁症（PPD）的女性可能会通过母乳将抗抑郁药暴露给婴儿。Brexanolone 是唯一被 FDA 批准用于治疗 PPD 的抗抑郁药。这项针对健康哺乳期志愿者的开放标签、Ib 期研究评估了 brexanolone 的药代动力学（PK）特性，并确定了哺乳期母亲的相对婴儿剂量（RID）。
12 名参与者接受了为期 60 小时的 brexanolone 输注（滴定至 90μg/kg/h）。在母乳和血浆中测量了 allopregnanolone 浓度。使用 PPD 患者和健康女性的非线性混合效应 PopPK 模型（N=156）计算 RID。通过参与者的综合数据集扩展模型结果至第 7 天。
母乳和血浆中的 allopregnanolone 浓度时间曲线相似（浓度梯度的分配系数[奶：血浆]为 1.36）。血浆中的平均（95%CI）C 为 89.7ng/mL（74.19-108.39），中位数（95%CI）t 为 47.8h（47.8-55.8）。总体 PK 特征最好由具有线性消除和分布的两室模型描述。体重是唯一确定的重要协变量。伴或不伴伴随抗抑郁治疗的参与者的 PopPK AUC 和 C 之间无明显差异。最大 RID 为 1.3%。
PopPK 模型成功描述了健康参与者母乳和血浆以及 PPD 患者 brexanolone 治疗的血浆中 allopregnanolone 的变异性和浓度时间曲线。allopregnanolone 从血浆和母乳中快速消除，RID 较低，提示 brexanolone 基于体重的剂量是合适的，并支持其他与 PK 相关的标签建议。
