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

Marija Pesic, Thomas Stöhr, Joachim Ossig, Keith Borkett, Martin Donsbach, Van-Anh Dao, Lynn Webster, Frank Schippers, Marija Pesic, Thomas Stöhr, Joachim Ossig, Keith Borkett, Martin Donsbach, Van-Anh Dao, Lynn Webster, Frank Schippers

Abstract

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.

Conflict of interest statement

Marija Pesic, Thomas Stöhr, Keith Borkett, Martin Donsbach, Van-Anh Dao, and Frank Schippers, as current or former employees of PAION, may own stocks or stock options of PAION. Lynn Webster is an employee at PRA Early Development Services, the CRO that conducted these two clinical trials.

Figures

Fig. 1
Fig. 1
Box and whisker plot including individual value plot of remimazolam AUC0–t and Cmax versus remimazolam and alcohol dose (results of trial 2). Box plots show 25–75 percentile and median values. Whisker plots indicate min and max values. AUC area under the curve, Cmax maximum observed plasma concentration, EtOH alcohol

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