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

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Trials

Background:

• Midazolam is a standard probe drug for assessing cytochrome P450 3A enzyme activity.
• Microdosed midazolam is increasingly utilized for drug phenotyping.
• Buccal administration offers potential advantages, but buccal absorption requires investigation.

Purpose of the Study:

• To determine the absolute bioavailability of microdosed midazolam following buccal administration.
• To evaluate the impact of buccal exposure time on midazolam's pharmacokinetic profile.
• To establish the relationship between buccal exposure duration and midazolam bioavailability.

Main Methods:

• A single-center, open-label clinical trial involving 12 healthy volunteers.
• Administration of 10 μg midazolam via a drinking solution and buccal formulation.
• Assessment of midazolam plasma concentrations and calculation of area under the curve (AUC) with varying buccal exposure times (0, 100, 150 seconds).

Main Results:

• Midazolam exposure (AUC) increased with buccal exposure time, plateauing at 100 seconds.
• Absolute bioavailability rose from 27.8% (drinking solution) to 66.1% (100-second buccal exposure).
• A Hill equation modeled the time-dependent bioavailability, with a maximal bioavailability of 64.5%.

Conclusions:

• Midazolam bioavailability is significantly influenced by buccal exposure duration.
• Even brief buccal exposure enhances midazolam absorption and bioavailability.
• These findings are critical for optimizing buccal midazolam administration in drug phenotyping.