Division of System Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.
Br J Clin Pharmacol. 2022 Oct;88(10):4387-4402. doi: 10.1111/bcp.15372. Epub 2022 Jun 16.
Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling.
For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions.
Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin-6 (IL-6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases.
This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target- and disease-specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL-6, Tumor Necrosis Factor alfa (TNF-α) and interleukin-1 bèta (IL-1β) in diseases with systemic inflammation.
免疫调节治疗药物的使用可能会通过逆转细胞色素 P450 酶代谢能力的炎症驱动改变，导致疾病-药物-药物相互作用（DDDIs）。欧洲药品管理局（EMA）和美国食品和药物管理局（FDA）于 2007 年发布的指南建议评估治疗性蛋白的 DDDI 潜力。本系统分析旨在描述免疫调节药物的可用 DDDI 试验、DDDI 风险的实验证据以及 FDA/EMA 批准药物标签中报告的 DDDI 风险信息。
为了进行这项系统综述，使用了 EMA 人用药品欧洲公共评估报告清单，选择了 2007 年后上市的、有 DDDI 风险的免疫调节单克隆抗体（mAbs）和酪氨酸激酶抑制剂（TKIs）。选定的药物被纳入 PubMed 和 Embase 搜索，以提取报告的相互作用研究。随后，使用产品特性摘要（SPCs）和美国处方信息（USPIs）分析 DDDI 风险描述。
对 24 种 mAbs 中的 12 种（50%）进行了评估 DDDI 风险的临床相互作用研究，而对 TKI 则没有。四项研究确定了 DDDI 风险，其中三项是针对白细胞介素-6（IL-6）中和 mAbs 的研究。基于（非）临床数据，在 32%的 SPCs 和 60%的 USPIs 中报告了 DDDI 风险。在 20 个案例中，有 35%的 EMA/FDA 文档与 DDDI 风险潜力一致。
这项系统综述进一步证实，免疫调节药物的 DDDI 风险具有靶向性和疾病特异性。药物标签信息将针对中和白细胞介素-6（IL-6）、肿瘤坏死因子阿尔法（TNF-α）和白细胞介素-1β（IL-1β）作用的 mAbs 标记为最大的 DDDI 风险，这些 mAbs 用于具有全身炎症的疾病。
