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

• Verfasst von: Wiebe, Sabrina [VerfasserIn]
• Verfasst von: Huennemeyer, Andreas [VerfasserIn]
• Verfasst von: Kadus, Werner Uli [VerfasserIn]
• Verfasst von: Goettel, Markus [VerfasserIn]
• Verfasst von: Jambrecina, Alen [VerfasserIn]
• Verfasst von: Schultz, Armin [VerfasserIn]
• Verfasst von: Vinisko, Richard [VerfasserIn]
• Verfasst von: Schlieker, Laura [VerfasserIn]
• Verfasst von: Herich, Lena [VerfasserIn]
• Verfasst von: Mikus, Gerd [VerfasserIn]
• Titel: Midazolam microdosing applied in early clinical development for drug-drug interaction assessment
• Verf.angabe: Sabrina T. Wiebe, Andreas Huennemeyer, Werner Kadus, Markus Goettel, Alen Jambrecina, Armin Schultz, Richard Vinisko, Laura Schlieker, Lena Herich, Gerd Mikus
• Jahr: 2021
• Jahr des Originals: 2020
• Umfang: 11 S.
• Fussnoten: First published: 20 May 2020 ; Gesehen am 19.04.2021
• Titel Quelle: Enthalten in: British journal of clinical pharmacology
• Ort Quelle: Oxford : Wiley-Blackwell, 1974
• Jahr Quelle: 2021
• Band/Heft Quelle: 87(2021), 1, Seite 178-188
• ISSN Quelle: 1365-2125
• DOI: doi:10.1111/bcp.14389
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: CYP3A
• Sach-SW: drug-drug interactions
• Sach-SW: early clinical development
• Sach-SW: microdosing
• Sach-SW: midazolam
• K10plus-PPN: 1755326122
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

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.