Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, The Netherlands.
Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Clin Pharmacol Ther. 2020 Aug;108(2):338-349. doi: 10.1002/cpt.1834. Epub 2020 Apr 23.
This study aimed to determine to which extent data on potential pharmacogenetic-pharmacokinetic (PG-PK) interactions are provided to, and assessed by, the European Medicines Agency (EMA) in novel drug marketing authorization applications (MAAs), and whether regulatory assessment of PG-PK interactions is adequate or could be optimized. For this purpose, we retrospectively analyzed MAAs of small molecule drugs assessed by the EMA between January 2014 and December 2017. As per two key requirements in the EMA's guideline, we analyzed cases where (i) a single functionally polymorphic drug metabolizing enzyme (DME) metabolizes > 25% of the drug, or (ii) the drug's PK shows high interindividual variability not explained by other factors than PG. Results showed that, of 113 drugs analyzed, 53 (47%) had ≥ 1 functionally polymorphic DME accounting for > 25% of the drug's metabolism, yielding 55 gene-drug pairs. For 36 of 53 (68%) of the products, CYP3A4 was the major DME. Compliance with European Union (EU) guidance on PG-PK issues in drug development was notably different for CYP3A4 substrates vs. non-CYP3A4 substrates. Adequate PG-PK data were provided during registration in 89% (16/18) of cases concerning non-CYP3A4 substrates, compared with 32% (12/37) of cases concerning CYP3A4 substrates. Concluding, PG-PK interactions related to non-CYP3A4 substrate drugs were, in general, addressed adequately in EU MAAs. PG-PK information on CYP3A4 substrates was available less frequently, despite some available evidence on the functional relevance of CYP3A4 polymorphisms. A more harmonized approach toward assessment of PG-PK issues in EU MAAs seems warranted, and a discussion on the relevance of CYP3A4 polymorphisms, such as CYP3A4*22, is recommended.
本研究旨在确定在新型药物上市许可申请（MAA）中，欧洲药品管理局（EMA）提供了多少潜在的药物遗传学-药物动力学（PG-PK）相互作用的数据，并对其进行了评估，以及 PG-PK 相互作用的监管评估是否充分或可以优化。为此，我们回顾性分析了 2014 年 1 月至 2017 年 12 月 EMA 评估的小分子药物的 MAA。根据 EMA 指南中的两个关键要求，我们分析了以下两种情况：（i）单一功能多态性药物代谢酶（DME）代谢超过药物的 25%，或（ii）药物的 PK 表现出高个体间变异性，无法用除 PG 以外的其他因素解释。结果表明，在分析的 113 种药物中，有 53 种（47%）具有至少一种功能多态性 DME，占药物代谢的 25%以上，产生 55 个基因-药物对。在 53 种产品中的 36 种（68%）中，CYP3A4 是主要的 DME。在药物开发中 PG-PK 问题方面，CYP3A4 底物与非 CYP3A4 底物的欧盟指南的合规性明显不同。在非 CYP3A4 底物相关的 18 个案例中，有 89%（16/18）在注册期间提供了充分的 PG-PK 数据，而 CYP3A4 底物相关的 37 个案例中，仅有 32%（12/37）提供了充分的数据。总的来说，在欧盟的 MAA 中，一般都充分考虑了与非 CYP3A4 底物药物相关的 PG-PK 相互作用。尽管有一些关于 CYP3A4 多态性功能相关性的证据，但关于 CYP3A4 底物的 PG-PK 信息提供得较少。似乎有必要在欧盟的 MAA 中采取更协调的方法来评估 PG-PK 问题，并建议讨论 CYP3A4 多态性（如 CYP3A4*22）的相关性。
