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.

中文翻译：

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接受 Brexanolone 注射的健康志愿者的母乳和血浆中的 Allopregnanolone 浓度，以及潜在相对婴儿剂量的群体药代动力学模型

背景与目的

患有产后抑郁症 (PPD) 的女性可能会通过母乳让她们的婴儿接触抗抑郁药。Brexanolone 是唯一获得 FDA 批准的抗抑郁药，专门用于治疗 PPD。这项针对健康哺乳志愿者的开放标签 Ib 期研究评估了 brexanolone 的药代动力学 (PK) 特性，并且群体 PK (PopPK) 模型确定了母乳喂养母亲的相对婴儿剂量 (RID)。

方法

12 名参与者接受了 60 小时的 brexanolone 输注（滴定至 90 µg/kg/h）。测量母乳和血浆中的异孕酮浓度。RID 是使用 PPD 患者和健康女性 ( N  = 156) 的非线性混合效应 PopPK 模型计算的。模型结果在参与者的综合数据集中扩展到第 7 天。

结果

Allopregnanolone 浓度-时间曲线在母乳和血浆之间相似（浓度梯度分配系数 [牛奶：血浆] 1.36）。血浆中的平均 (95% CI) C _max为 89.7 ng/mL (74.19–108.39)，中位 (95% CI) t _max为 47.8 h (47.8–55.8)。整体 PK 曲线最好用线性消除和分布的两室模型来描述。体重是唯一确定的显着协变量。有或没有伴随抗抑郁治疗的参与者之间的 PopPK AUC 和C _max没有明显差异。最大 RID 为 1.3%。

结论

PopPK 模型成功地描述了健康参与者的母乳和血浆中以及接受 brexanolone 治疗的 PPD 患者血浆中别孕醇酮的变异性和浓度-时间曲线。从血浆和母乳中快速消除异孕酮，以及低 RID，表明基于体重的 brexanolone 给药是适当的，并支持其他与 PK 相关的标签建议。