Absolute bioavailability of microdosed midazolam after buccal administration is dependent on buccal exposure time

• Verfasst von: Grass, Jana [VerfasserIn]
• Verfasst von: Rose, Peter [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Verfasst von: Blank, Antje [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Mikus, Gerd [VerfasserIn]
• Titel: Absolute bioavailability of microdosed midazolam after buccal administration is dependent on buccal exposure time
• Verf.angabe: Jana Grass, Peter Rose, Jürgen Burhenne, Antje Blank, Walter Emil Haefeli, and Gerd Mikus
• Jahr: 2021
• Umfang: 8 S.
• Fussnoten: First published: 25 September 2020 ; Gesehen am 13.12.2021
• Titel Quelle: Enthalten in: Journal of clinical pharmacology
• Ort Quelle: Hoboken, NJ : Wiley, 1961
• Jahr Quelle: 2021
• Band/Heft Quelle: 61(2021), 4, Seite 472-479
• ISSN Quelle: 1552-4604
• DOI: doi:10.1002/jcph.1751
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: bioavailability
• Sach-SW: buccal
• Sach-SW: CYP3A
• Sach-SW: midazolam
• K10plus-PPN: 1782023895
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

Midazolam is an established probe drug to assess cytochrome P450 3A activity (phenotyping). Microdosed midazolam is increasingly used for this purpose; a buccal formulation might be of advantage, but buccal absorption might occur. We therefore tested in a single-center, open-label clinical trial with 12 healthy volunteers the absolute bioavailability of 10 μg of midazolam after buccal administration in relation to buccal exposure time. In relation to a drinking solution, there was an increase of midazolam exposure (area under the plasma concentration-time curve from time 0 to infinity) with increasing buccal exposure time with an apparent saturation at 100-second buccal exposure. Absolute bioavailability increased from 27.8% (95% confidence interval, 23.5-32.9) for the drinking solution (0 seconds) to 66.1% (95% confidence interval, 60.0-72.8) after 100-second buccal exposure with no further increase after 150 seconds. A Hill equation described the time dependency of midazolam bioavailability with maximal bioavailability as 64.5% and buccal exposure time resulting in half maximal bioavailability increase as 16 seconds. In conclusion, midazolam bioavailability is highly dependent on buccal exposure time, and even a few seconds of buccal exposure will increase bioavailability due to buccal absorption. This needs to be taken into account for any buccal administration of midazolam.