Transfer of Intravenous Remimazolam into Milk of Lactating Sheep and Uptake by Breast-fed Lambs

Introduction: Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, infor-mation on the extent and possible risks of remimazolam passing through a mother´s milk to the infant is needed. The objective of this work was to study the transfer of remimazolam from maternal to infant circula-tion by mother´s milk in an animal model. Methods: Three lactating British milk sheep received intravenous remimazolam (0.4 mg/kg bolus plus 4-hr-infusion at 1 or 2 mg/kg/hour). Drug profiles were recorded in plasma and milk. Six suckling lambs were administered remimazolam by intravenous and oral gavage administration for a comparison of plasma con-centration profiles of remimazolam and its primary metabolite, CNS7054. Results: Treatment of lactating sheep induced dose-dependent sedation and loss of consciousness. At the end of infusion, the concentration of remimazolam was higher in milk than in plasma. The subsequent elimination of remimazolam from milk was rapid, although somewhat slower than from plasma. Discussions: In lambs, intravenous, but not oral, remimazolam (2 mg) caused different grades of sedation/an-esthesia (fully reversible within 8 to 15 min). Mean plasma Cmax was 278.3 ng/mL after intravenous and 1.3 ng/mL after oral administration. Oral gavage resulted in a sizable plasma concentration of CNS7054 (Cmax around 100 ng/mL), indicating efficient intestinal absorption of the parent drug, followed by extensive first-pass metabolic elimination, leading to negligible bioavailability of oral remimazolam. Conclusion: In mother´s milk, remimazolam reaches higher concentrations than in plasma and is cleared by redistribution to the central compartment for final hepatic elimination. In lambs, oral remimazolam results in minimal plasma concentrations, suggesting that safety concerns regarding breast-fed infants would be minor and could be completely alleviated by a short nursing interruption.