Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time

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 mu g 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.