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Review
. 2024 Sep;64(9):1123-1129.
doi: 10.1002/jcph.2447. Epub 2024 May 26.

Value of Assessing 1-Hydroxymidazolam in Drug-Drug Interaction Studies with Midazolam as a Substrate of Cytochrome P450 3A

Massimo Magliocca  1 , Benjamin Berger  1 , Vincent Lemoine  1 , Priska Kaufmann  1 , Jasper Dingemanse  1
Affiliations
Review

Value of Assessing 1-Hydroxymidazolam in Drug-Drug Interaction Studies with Midazolam as a Substrate of Cytochrome P450 3A

Massimo Magliocca et al. J Clin Pharmacol. 2024 Sep.

Abstract

The purpose of this overview was to perform an exploratory analysis of in-house drug-drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1-OH-midazolam (1-OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1-OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1-OHM, an increase in midazolam and a decrease in 1-OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1-OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1-OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator.

Keywords: 1‐OH‐midazolam; CYP3A; drug‐drug interaction; midazolam; pharmacokinetics.

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