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

Midazolam microdosing applied in early clinical development for drug-drug interaction assessment / Sabrina T. Wiebe, Andreas Huennemeyer, Werner Kadus, Markus Goettel, Alen Jambrecina, Armin Schultz, Richard Vinisko, Laura Schlieker, Lena Herich, Gerd Mikus

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..

Medienart:	E-Artikel

Erscheinungsjahr:	2021
Erschienen:	2021

Enthalten in:	Zur Gesamtaufnahme - volume:87
Enthalten in:	British journal of clinical pharmacology - 87(2021), 1, Seite 178-188

Sprache:	Englisch

Beteiligte Personen:	Wiebe, Sabrina [VerfasserIn] Huennemeyer, Andreas [VerfasserIn] Kadus, Werner Uli, 1959- [VerfasserIn] Goettel, Markus [VerfasserIn] Jambrecina, Alen, 1971- [VerfasserIn] Schultz, Armin, 1956- [VerfasserIn] Vinisko, Richard [VerfasserIn] Schlieker, Laura [VerfasserIn] Herich, Lena [VerfasserIn] Mikus, Gerd [VerfasserIn]

Links:	Volltext [kostenfrei] Volltext [kostenfrei]

Themen:	CYP3A Drug-drug interactions Early clinical development Microdosing Midazolam

Anmerkungen:	First published: 20 May 2020 Gesehen am 19.04.2021

Umfang:	11

doi:	10.1111/bcp.14389

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1755326122

Internformat


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520			\|a 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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Midazolam microdosing applied in early clinical development for drug-drug interaction assessment / Sabrina T. Wiebe, Andreas Huennemeyer, Werner Kadus, Markus Goettel, Alen Jambrecina, Armin Schultz, Richard Vinisko, Laura Schlieker, Lena Herich, Gerd Mikus

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