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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 (AUC0–∞, Cmax) during administration with the test substances was compared to baseline data via an analysis of variance on log‐transformed data. Partial AUC2–4 ratios were also compared to AUC0–∞ ratios using linear regression on log‐transformed data. Results: Test compound Cmax 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 AUC0–∞ 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. Cmax gMean ratios were in the same range. Thus, no relevant drug–drug interactions were evident, based on the results of midazolam microdosing. AUC2–4 ratios from these studies were comparable to the AUC0–∞ 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. [ABSTRACT FROM AUTHOR]

Direct comparisons between skin absorption data and clinical pharmacokinetic data are rare. Here we use the lipophilic nonsteroidal selective glucocorticoid receptor agonist BAY1003803 to make such a comparison. The objective is to find the extent to which measurements of skin permeation in vitro can be used to predict the corresponding permeation in vivo for human pharmacokinetics of topically applied substances. BAY1003803 was prepared in various formulations: ointment, hydrophilic cream, lipophilic cream, and milk. Its ability to permeate healthy human skin was measured in vitro in static diffusion cells, and percutaneous absorption as well as dermal delivery was measured thereafter, for 2 selected formulations, in vivo in healthy volunteers. Absorption in vivo comparing ointment and lipophilic cream was correlated with expectation based on the dermal delivery obtained in vitro. A 2.17‐fold higher systemic exposure to BAY1003803 was achieved by the ointment formulation. This is well in line with the predicted exposure difference of 2.74 based on the in vitro data. In conclusion, in vitro skin absorption studies using human skin are suitable for the prediction of systemic exposure and formulation effects in vivo; they can therefore be applied to guide the design of clinical investigations of dermatological preparations. [ABSTRACT FROM AUTHOR]