Cargando…

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

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, espe...

Descripción completa

Detalles Bibliográficos
Autores principales: Pesic, Marija, Stöhr, Thomas, Ossig, Joachim, Borkett, Keith, Donsbach, Martin, Dao, Van-Anh, Webster, Lynn, Schippers, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419402/
https://www.ncbi.nlm.nih.gov/pubmed/32757149
http://dx.doi.org/10.1007/s40268-020-00317-0
_version_ 1783569876351188992
author Pesic, Marija
Stöhr, Thomas
Ossig, Joachim
Borkett, Keith
Donsbach, Martin
Dao, Van-Anh
Webster, Lynn
Schippers, Frank
author_facet Pesic, Marija
Stöhr, Thomas
Ossig, Joachim
Borkett, Keith
Donsbach, Martin
Dao, Van-Anh
Webster, Lynn
Schippers, Frank
author_sort Pesic, Marija
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40268-020-00317-0) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-7419402
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-74194022020-08-18 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 Pesic, Marija Stöhr, Thomas Ossig, Joachim Borkett, Keith Donsbach, Martin Dao, Van-Anh Webster, Lynn Schippers, Frank Drugs R D Original Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40268-020-00317-0) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-08-05 2020-09 /pmc/articles/PMC7419402/ /pubmed/32757149 http://dx.doi.org/10.1007/s40268-020-00317-0 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Original Research Article
Pesic, Marija
Stöhr, Thomas
Ossig, Joachim
Borkett, Keith
Donsbach, Martin
Dao, Van-Anh
Webster, Lynn
Schippers, Frank
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419402/
https://www.ncbi.nlm.nih.gov/pubmed/32757149
http://dx.doi.org/10.1007/s40268-020-00317-0
work_keys_str_mv AT pesicmarija remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT stohrthomas remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT ossigjoachim remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT borkettkeith remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT donsbachmartin remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT daovananh remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT websterlynn remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials
AT schippersfrank remimazolamhasloworalbioavailabilityandnopotentialformisuseindrugfacilitatedsexualassaultswithorwithoutalcoholresultsfromtworandomisedclinicaltrials