RESUMO
Cytochrome P450 3A (CYP3A) isozymes metabolize about 50% of all marketed drugs. Their activity can be modulated up to 400-fold, which has great impact on individual dose requirements for CYP3A substrates. The activity of CYP3A can be monitored using the CYP3A substrate midazolam. To avoid pharmacological midazolam effects during phenotyping, a microdosing approach is preferred. However, the preparation of microdosed dosage forms remains a challenge. Fast dissolving buccal films are therefore proposed to facilitate this task. It was the aim of the present study to clinically evaluate a novel buccal film containing microdoses of midazolam for assessment of CYP3A activity. In a randomized, open-label crossover design, the pharmacokinetics of midazolam and its active hydroxy-metabolite, 1'OHmidazolam, was assessed in 12â¯healthy volunteers after administration of single microdoses of midazolam (30⯵g) as buccal film or buccal solution. The buccal film did rapidly disintegrate, was well tolerated, and no adverse events occurred. The film and the solution showed very similar midazolam plasma concentration-time profiles but were not bioequivalent according to EMA and FDA guidelines. For Cmax, AUC0-12h, and AUC0-∞ the geometric mean ratios of film to solution, with their 90% confidence intervals in parentheses, were 1.15 (1.00-1.32), 1.16 (1.04-1.28), and 1.19 (1.08-1.31), respectively. As a proxy for CYP3A activity, molar metabolic ratios of midazolam and 1'OHmidazolam were analyzed over time, which revealed good correlations already 1â¯h or 2â¯h after application of the film or the solution, respectively. The tested midazolam buccal film is a convenient dosage form that facilitates administration of a phenotyping probe considerably and may potentially be used in special patient populations such as pediatric patients. Clinical Trials.gov Identifier: NCT03204578.