Wang Lei, Shendre Aditi, Chiang Chien-Wei, Cao Weidan, Ning Xia, Zhang Ping, Zhang Pengyue, Li Lang
Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA.
Now at Indiana University School of Medicine, Indianapolis, IN, USA.
Br J Clin Pharmacol. 2022 Feb;88(4):1471-1481. doi: 10.1111/bcp.14762. Epub 2021 Feb 23.
While the pharmacokinetic (PK) mechanisms for many drug interactions (DDIs) have been established, pharmacovigilance studies related to these PK DDIs are limited. Using a large surveillance database, a translational informatics approach can systematically screen adverse drug events (ADEs) for many DDIs with known PK mechanisms.
We collected a set of substrates and inhibitors related to the cytochrome P450 (CYP) isoforms, as recommended by the United States Food and Drug Administration (FDA) and Drug Interactions Flockhart table™. The FDA's Adverse Events Reporting System (FAERS) was used to obtain ADE reports from 2004 to 2018. The substrate and inhibitor information were used to form PK DDI pairs for each of the CYP isoforms and Medical Dictionary for Regulatory Activities (MedDRA) preferred terms used for ADEs in FAERS. A shrinkage observed-to-expected ratio (Ω) analysis was performed to screen for potential PK DDI and ADE associations.
We identified 149 CYP substrates and 62 CYP inhibitors from the FDA and Flockhart tables. Using FAERS data, only those DDI-ADE associations were considered that met the disproportionality threshold of Ω > 0 for a CYP substrate when paired with at least two inhibitors. In total, 590 ADEs were associated with 2085 PK DDI pairs and 38 individual substrates, with ADEs overlapping across different CYP substrates. More importantly, we were able to find clinical and experimental evidence for the paclitaxel-clopidogrel interaction associated with peripheral neuropathy in our study.
In this study, we utilized a translational informatics approach to discover potentially novel CYP-related substrate-inhibitor and ADE associations using FAERS. Future clinical, population-based and experimental studies are needed to confirm our findings.
虽然许多药物相互作用（DDIs）的药代动力学（PK）机制已经明确，但与这些PK DDIs相关的药物警戒研究却很有限。利用大型监测数据库，一种转化信息学方法可以系统地筛查许多具有已知PK机制的药物相互作用导致的不良药物事件（ADEs）。
我们按照美国食品药品监督管理局（FDA）和药物相互作用Flockhart表™的建议，收集了一组与细胞色素P450（CYP）亚型相关的底物和抑制剂。使用FDA的不良事件报告系统（FAERS）获取2004年至2018年的ADE报告。底物和抑制剂信息用于为每种CYP亚型形成PK DDI对，以及用于FAERS中ADEs的医学监管活动词典（MedDRA）首选术语。进行收缩观察与预期比率（Ω）分析以筛查潜在的PK DDI和ADE关联。
我们从FDA和Flockhart表中识别出149种CYP底物和62种CYP抑制剂。利用FAERS数据，仅考虑那些与至少两种抑制剂配对时CYP底物的Ω>0的不成比例阈值的DDI-ADE关联。总共590例ADEs与2085对PK DDI和38种个体底物相关，不同CYP底物的ADEs存在重叠。更重要的是，在我们的研究中，我们能够找到与周围神经病变相关的紫杉醇-氯吡格雷相互作用的临床和实验证据。
在本研究中，我们利用转化信息学方法，通过FAERS发现了潜在的新型CYP相关底物-抑制剂和ADE关联。未来需要进行临床、基于人群和实验研究来证实我们的发现。
