Beschreibung:
<jats:sec><jats:title>Aims</jats:title><jats:p>We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug–drug interaction liability.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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<jats:sub>0–∞</jats:sub>, <jats:italic>C</jats:italic><jats:sub>max</jats:sub>) during administration with the test substances was compared to baseline data via an analysis of variance on log‐transformed data. Partial AUC<jats:sub>2–4</jats:sub> ratios were also compared to AUC<jats:sub>0–∞</jats:sub> ratios using linear regression on log‐transformed data.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Test compound <jats:italic>C</jats:italic><jats:sub>max</jats:sub> 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<jats:sub>0–∞</jats:sub> 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. <jats:italic>C</jats:italic><jats:sub>max</jats:sub> gMean ratios were in the same range. Thus, no relevant drug–drug interactions were evident, based on the results of midazolam microdosing. AUC<jats:sub>2–4</jats:sub> ratios from these studies were comparable to the AUC<jats:sub>0–∞</jats:sub> ratios.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec>