Pre-Clinical Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
Drug Metab Pharmacokinet. 2009;24(6):500-10. doi: 10.2133/dmpk.24.500.
A method of assessing the risk of drug-drug interaction (DDI) caused by mechanism-based inhibition (MBI) was developed for early-stage drug development using cytochrome P450 (CYP) 3A4 inhibition screening data. CYP3A4 inhibition was evaluated using a fluorescent substrate with or without preincubation containing an inhibitor. The results showed that five well-known mechanism-based inhibitors, but not the competitive inhibitor ketoconazole, had lower IC(50) after preincubation, suggesting the utility of the IC(50) shift by preincubation to discern mechanism-based inhibitors. A method to approximately predict the change in the area under the concentration-time curve (AUC) of a co-administered drug by MBI was found using IC(50) shift data and the unbound mean plasma concentration of the inhibitor. From our predictions of change in the AUC for 38 drugs using this method, all mechanism-based inhibitors causing change in the AUC of more than 200% were predicted to be high risk. In conclusion, our method provides a simple assessment of the risk of DDI from mechanism-based inhibitors, especially in the early stages of drug development.
建立了一种使用细胞色素 P450（CYP）3A4 抑制筛选数据评估基于机制的抑制（MBI）引起的药物-药物相互作用（DDI）风险的方法。使用含有抑制剂的无预孵育或预孵育的荧光底物评估 CYP3A4 抑制作用。结果表明，五种已知的基于机制的抑制剂，但不是竞争性抑制剂酮康唑，在预孵育后具有更低的 IC（50），表明预孵育的 IC（50）偏移可用于区分基于机制的抑制剂。使用 IC（50）偏移数据和抑制剂的游离平均血浆浓度，发现了一种大约预测共给药药物的浓度-时间曲线下面积（AUC）变化的方法。使用该方法预测 38 种药物的 AUC 变化，预测所有导致 AUC 变化超过 200％的基于机制的抑制剂均为高风险。总之，我们的方法提供了一种简单的基于机制的抑制剂引起的 DDI 风险评估方法，特别是在药物开发的早期阶段。
