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Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time
Author(s) -
Grass Jana,
Rose Peter,
Burhenne Jürgen,
Blank Antje,
Haefeli Walter Emil,
Mikus Gerd
Publication year - 2021
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1751
Subject(s) - buccal administration , bioavailability , midazolam , pharmacology , medicine , sedation
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.