Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film

Eur J Pharm Sci. 2019 Jul 1:135:77-82. doi: 10.1016/j.ejps.2019.05.010. Epub 2019 May 16.


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'‑OH‑midazolam, was assessed in 12 healthy volunteers after administration of single microdoses of midazolam (30 μg) 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'‑OH‑midazolam were analyzed over time, which revealed good correlations already 1 h or 2 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.

Keywords: Buccal film; CYP3A; Microdosing; Midazolam; Pharmacokinetics; Phenotyping.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Buccal
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / adverse effects
  • Anti-Anxiety Agents / pharmacokinetics*
  • Area Under Curve
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism*
  • Drug Compounding
  • Drug Interactions
  • Female
  • Humans
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / adverse effects
  • Hypnotics and Sedatives / pharmacokinetics*
  • Male
  • Midazolam / administration & dosage
  • Midazolam / adverse effects
  • Midazolam / pharmacokinetics*
  • Oral Mucosal Absorption


  • Anti-Anxiety Agents
  • Hypnotics and Sedatives
  • Cytochrome P-450 CYP3A
  • Midazolam

Associated data

  • ClinicalTrials.gov/NCT03204578