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 sign...
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| Hauptverfasser: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2021
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| In: |
British journal of clinical pharmacology
Year: 2020, Jahrgang: 87, Heft: 1, Pages: 178-188 |
| ISSN: | 1365-2125 |
| DOI: | https://doi.org/10.1111/bcp.14389 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/https://doi.org/10.1111/bcp.14389 Verlag, kostenfrei, Volltext: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14389 
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| Verfasserangaben: | Sabrina T. Wiebe, Andreas Huennemeyer, Werner Kadus, Markus Goettel, Alen Jambrecina, Armin Schultz, Richard Vinisko, Laura Schlieker, Lena Herich, Gerd Mikus |
| Zusammenfassung: | 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. |
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| Beschreibung: | First published: 20 May 2020 Gesehen am 19.04.2021 |
| Beschreibung: | Online Resource |
| ISSN: | 1365-2125 |
| DOI: | https://doi.org/10.1111/bcp.14389 |