Midazolam microdosing applied in early clinical development for drug-drug interaction assessment
Sabrina T Wiebe1,2, Andreas Huennemeyer2, Werner Kadus2
1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
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.
Insights
Midazolam microdosing in early clinical trials effectively assessed drug-drug interaction risks without significant subject burden. This method reduces the need for extensive drug-drug interaction studies, saving time and resources.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Drug Development
Background:
- Drug-drug interactions (DDIs) are a significant concern in drug development.
- Early assessment of CYP3A-mediated DDIs is crucial for identifying potential risks.
- Traditional DDI studies can be resource-intensive and increase subject burden.
Purpose of the Study:
- To evaluate the feasibility of using a midazolam microdose in early clinical studies for assessing CYP3A DDI liability.
- To determine if midazolam microdosing can reduce the need for dedicated DDI studies.
Main Methods:
- Three early clinical studies were conducted using compounds with in vitro CYP3A perpetrator signals.
- A microdose of midazolam was administered alone and then with increasing doses of test compounds (A, B, C).
- Midazolam exposure (AUC, Cmax) was compared to baseline to assess DDI potential using statistical analyses.
Main Results:
- Midazolam microdosing revealed no relevant CYP3A-mediated drug-drug interactions for compounds A, B, and C.
- Compound C showed Cmax values exceeding interaction thresholds, but midazolam microdosing analysis indicated no significant interaction.
- AUC and Cmax ratios were comparable between microdosing and traditional assessment methods.
Conclusions:
- Midazolam microdosing is a viable tool for early clinical assessment of CYP3A DDI liability.
- Incorporating microdosing reduces subject burden and the necessity for dedicated DDI studies.
- Further optimization, such as limited sampling, could enhance efficiency and reduce costs.
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