Midazolam microdosing applied in early clinical development for drug-drug interaction assessment
© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
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 |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:87 |
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| Enthalten in: |
British journal of clinical pharmacology - 87(2021), 1 vom: 01. Jan., Seite 178-188 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wiebe, Sabrina T [VerfasserIn] |
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| Links: |
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| Themen: |
CYP3A |
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| Anmerkungen: |
Date Completed 28.07.2021 Date Revised 28.07.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.14389 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM310185556 |
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| 500 | |a Date Revised 28.07.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a CYP3A | |
| 650 | 4 | |a drug-drug interactions | |
| 650 | 4 | |a early clinical development | |
| 650 | 4 | |a microdosing | |
| 650 | 4 | |a midazolam | |
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| 700 | 1 | |a Huennemeyer, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Kadus, Werner |e verfasserin |4 aut | |
| 700 | 1 | |a Goettel, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Jambrecina, Alen |e verfasserin |4 aut | |
| 700 | 1 | |a Schultz, Armin |e verfasserin |4 aut | |
| 700 | 1 | |a Vinisko, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Schlieker, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Herich, Lena |e verfasserin |4 aut | |
| 700 | 1 | |a Mikus, Gerd |e verfasserin |4 aut | |
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