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

Abstract

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.

Clinical Lactation Studies of Neuropsychiatric Medications: Clinical Pharmacology and Labeling Considerations

“…The RID was computed using a nonlinear mixed‐effects population PK model of patients with postpartum depression and healthy individuals 16 . The results of this study were later published in a peer‐reviewed journal 17 …”

“…16 The results of this study were later published in a peer-reviewed journal. 17 Upon review of the pharmaceutical company's lactation study, the FDA determined that the information regarding the presence and amount of brexanolone in human milk was adequate for inclusion in brexanolone labeling at the time of initial FDA approval in 2019. 16 Currently approved brexanolone labeling notes the following in the Risk Summary: "Brexanolone is transferred to breastmilk in nursing mothers.…”

The value of midwifery counseling during lactation as a key factor of pharmacovigilance

“…Population pharmacokinetic (pop PK) modeling, for example, provides evaluations on infant drug exposure via breast milk through simulation. Preliminary results obtained from studies using pop PK modeling enhance the validity of the model-based simulations [12][13][14] .…”

Simultaneous Determination of Selected Steroids with Neuroactive Effects in Human Serum by Ultrahigh-Performance Liquid Chromatography–Tandem Mass Spectrometry

“…However, the developed method can be reliably applied to some physiological conditions in which natural levels increase several-fold. For example, the level of ALLO fluctuates in women of reproductive age from less than 1 to 5 nmol/L (depending on the phase of the menstrual cycle); at the end of the third trimester of pregnancy, its level can even reach almost 160 nmol/L. , …”

“…However, it is recommended to use the matrix surrogate calibration curve for the analysis of metabolites in biological samples. 86 Compared to many available studies, LLOQ values for T, 34,39,47,81,82,85 DHEA, 35,39,41,45,47,81,82,85 PROG, 35,39,41,44,47 PREG, 39,47 ANDRO, 39,41,81,82,85 ALLO, 88,89 and DHT 39 were better or at least within 1 order of magnitude. Lower quantification limits for some substances in other methods may be due to the use of different ionization techniques.…”