Remimazolam Has Low Oral Bioavailability and No Potential for Misuse in Drug-Facilitated Sexual Assaults, with or Without Alcohol: Results from Two Randomised Clinical Trials

• Published in: Drugs in R&D Vol. 20; no. 3; pp. 267 - 277
• Main Authors: Pesic, Marija, Stöhr, Thomas, Ossig, Joachim, Borkett, Keith, Donsbach, Martin, Dao, Van-Anh, Webster, Lynn, Schippers, Frank
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2020; Springer Nature B.V; Adis, Springer Healthcare
• Subjects: Administration, Oral; Adult; Alcohol; Alcoholic Beverages - adverse effects; Benzodiazepines; Benzodiazepines - administration & dosage; Benzodiazepines - adverse effects; Benzodiazepines - pharmacokinetics; Bioavailability; Biological Availability; Body mass index; Clinical trials; Consciousness; Cytochrome; Drug dosages; Enzymes; Female; Females; Healthy Volunteers; Humans; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - pharmacokinetics; Internal Medicine; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Original; Original Research Article; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Prescription Drug Misuse; Sex crimes; Sex Offenses - prevention & control; Young Adult
• ISSN: 1174-5886; 1179-6901; 1179-6901
• DOI: 10.1007/s40268-020-00317-0

Background and Objectives Remimazolam is a new ultra-short-acting benzodiazepine currently being developed for intravenous use in procedural sedation, general anaesthesia, and intensive care unit sedation. Benzodiazepines represent a drug class associated with drug-facilitated sexual assaults, especially in combination with alcohol. Two clinical trials were designed to evaluate the oral bioavailability and pharmacokinetics/pharmacodynamics of remimazolam and to assess the potential for remimazolam misuse in drug-facilitated sexual assaults via oral ingestion. Methods Trial 1 was conducted in 14 healthy volunteers to evaluate the oral bioavailability of remimazolam. Part 1 of trial 2 was conducted in 21 healthy female volunteers to find the minimal biologically active dose of oral remimazolam. Part 2 of trial 2 was conducted in 11 healthy female volunteers to evaluate the pharmacokinetics/pharmacodynamics of oral remimazolam in combination with alcohol. Results Remimazolam undergoes rapid and extensive first-pass metabolism upon oral administration. The oral bioavailability of remimazolam was negligible (2.2% based on total systemic exposure and 1.2% based on maximum plasma concentration). Plasma clearance of both remimazolam and its metabolite was fast (elimination half-life 20‒40 min and 1.75‒2 h, respectively). Alcohol did not appear to inhibit the rapid first-pass metabolism of remimazolam. No clear sedative effects were observed for remimazolam without alcohol. Significant sedation was observed in one of ten subjects after remimazolam 360 mg (18 drug product vials) + 40% v/v alcohol. Conclusion The oral bioavailability of remimazolam is negligible, which—together with its distinct bitter taste—suggests no meaningful potential for misuse in drug-facilitated sexual assaults via oral ingestion, with or without alcohol. Clinical Trial Registration Numbers Trial 1 (NCT04113564) and trial 2 (NCT04113343) both retrospectively registered on 2 October 2019.