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

Current Drug Metabolism, vol. 26, pp. 418–430

Abstract

INTRODUCTION: Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, information on the extent and possible risks of remimazolam being passed over to the infant through mother´s milk is needed. The objective of this work was to study the transfer of remimazolam from maternal to infant circulation by mother´s milk in an animal model. METHODS: Three lactating British milk sheep received intravenous remimazolam (0.4 mg/kg bolus plus 4-hrinfusion 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 concentration 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. DISCUSSION: 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 firstpass 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.

Authors 5

1. Wolfgang A. Schmalix corresponding

   Pharmalog (Germany)

   Affiliation as printed

   Schmalix PharmaConsult, Gröbenzell, Germany

2. Maureen Onyuro

   Ruhr University Bochum

   Affiliation as printed

   Institute of Pathology of the Ruhr-University, Bochum, Germany

3. Marija Pesic
   Affiliation as printed

   Formycon AG, Martinsried/Planegg, Germany

4. Karl‐Uwe Petersen Aachen Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Medical Faculty, RWTH Aachen University, Aachen, Germany

   Medical Faculty, RWTH Aachen University

5. Thomas Stoehr Aachen

   Paion (Germany)

   Affiliation as printed

   Paion Pharma GmbH Dept of R&D, Aachen, Germany

   Paion GmbH Dept of R&D, Aachen, Germany