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.
摘要：
本概述的目的是对研究药物和口服咪达唑仑进行的内部药物-药物相互作用（DDI）研究进行探索性分析，以评估在此类研究中测量1-OH-咪达唑仑（1-OHM）的价值。通过分析血浆中的咪达唑仑和1-OHM并评估其药代动力学参数，评估了研究药物对细胞色素P4503A（CYP3A）的作用。鉴于母体药物通过CYP3A几乎完全代谢为主要代谢产物1-OHM，预计在由作案药物引起的CYP3A抑制的情况下,咪达唑仑的增加和1-OHM暴露的减少.在CYP3A诱导的情况下预期相反。对于这个分析，纳入了8种不同研究药物的犯罪者潜力.在包括的10项研究中，根据咪达唑仑本身产生的数据对鉴定的CYP3A抑制剂（n=4）和诱导剂（n=1）进行分类，1-OHM水平对数据的解释没有贡献，因为它们不能证实母体化合物的发现。因此,结论是,继续分析血浆中的1-OHM可能值得怀疑,因为在以研究药物为作案者进行CYP3ADDI研究时,这并不能为结果的解释增加价值.
