Milk and plasma pharmacokinetics of single-dose ubrogepant in healthy lactating women.

Abstract

Objective: The objectives of this study were to evaluate the safety, plasma and milk pharmacokinetics, excretion in breast milk, and the relative infant dose of ubrogepant following a single oral dose.

Background: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. Preclinical findings in rats demonstrated comparable concentrations of ubrogepant in milk versus plasma; however, the quantification of ubrogepant excretion in human breast milk and breastfed infant exposure have not been previously evaluated.

Methods: This open-label, phase 1 study (NCT05892757) enrolled healthy, lactating adult women from July 11, 2023, to February 22, 2024. Participants were 1-6 months postpartum and received a single dose of ubrogepant 100 mg (2 × 50 mg tablets) orally. Plasma and breast milk samples were collected for up to 24 h after dosing to evaluate pharmacokinetics and ubrogepant concentrations were determined using validated liquid chromatography tandem mass spectrometry assays. Standard pharmacokinetic parameters were calculated from the plasma concentration and breast milk data using non-compartmental analyses. The milk-to-plasma concentration ratio was calculated based on the ratio of the area under the plasma concentration-time curve from time 0 to infinity (AUC_∞) of human milk to the AUC_∞ of plasma. The relative infant dose was calculated as 100 times the quotient of the body weight-normalized infant dose and the body weight-normalized maternal dose. Safety and tolerability were assessed via adverse events, vital signs, electrocardiograms, and clinical laboratory measurements.

Results: A total of 12 women were enrolled who each received a single dose of oral ubrogepant 100 mg. The mean milk-to-plasma ratio was 0.23, the cumulative amount of ubrogepant excreted in breast milk was <0.02% and the calculated relative infant dose was 0.15%. The maximum observed breast milk concentration and AUC of ubrogepant in breast milk were significantly lower (75% and 78%, respectively) compared to plasma. Only two mild adverse events were reported.

Conclusion: Less than 0.02 mg of a 100 mg dose of ubrogepant was excreted in breast milk over a 24-h period. The minimal transfer of ubrogepant into breast milk is not considered clinically relevant.