Midazolam microdosing applied in early clinical development for drug–drug interaction assessment

Aims We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug–drug interaction liability. Methods Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 μg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC 0–∞ , C max ) during administration with the test substances was compared to baseline data via an analysis of variance on log‐transformed data. Partial AUC 2–4 ratios were also compared to AUC 0–∞ ratios using linear regression on log‐transformed data. Results Test compound C max values exceeded relevant thresholds for drug–drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC 0–∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. C max gMean ratios were in the same range. Thus, no relevant drug–drug interactions were evident, based on the results of midazolam microdosing. AUC 2–4 ratios from these studies were comparable to the AUC 0–∞ ratios. Conclusion Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug–drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.