Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland.
Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland
Drug Metab Dispos. 2024 Feb 14;52(3):159-170. doi: 10.1124/dmd.123.001512.
Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small-molecule drugs and therefore, may impact the safety and efficacy of medicines in broad therapeutic areas. is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of present a unique challenge for academia, industry, and regulatory agencies alike due to the lack of feasibility of characterizing their clinical relevance in clinical trials, particularly in variants that exhibit population-specific frequencies in racial and ethnic groups that are poorly represented in clinical trials. Despite significant advancement in pharmacogenomics, the substrate specificity and related clinical relevance of these rare variants remain largely unclear, and further efforts are warranted to characterize the burden of these variants on adverse drug reactions and drug efficacy. Thus, cell-based in vitro systems can be used to inform substrate-specific effects and the overall relevance of a rare variant. Liver microsomes, cell-based expression systems, ex vivo primary samples, and purified variant protein have all been used with various substrates to potentially predict the clinical impact of new substrates. In this review, we identify rare variants of that demonstrate differences across races in prevalence and thus are often unassessed in clinical trials. Accordingly, we examine current pharmacogenomic in vitro models used to analyze the functional impact of these rare variants in a substrate-specific manner. SIGNIFICANCE STATEMENT: Variants of CYP2D6 play a clinically relevant role in drug metabolism, leading to potential safety and efficacy concerns. Although the influence of prevalent variants is often well characterized, rare variants are traditionally not included in clinical trials. This review captures the clinical relevance of rare variants in by highlighting in vitro models that analyze their impact on the metabolism of CYP2D6 substrates.
细胞色素 P450 2D6（CYP2D6）负责代谢多达 20%的小分子药物，因此可能会影响广泛治疗领域的药物安全性和疗效。该酶高度多态性，其变体的频率在不同种族和民族人群中存在差异，显著影响酶的功能和药物代谢。然而，由于在临床试验中难以确定其临床相关性，罕见的 CYP2D6 变体对学术界、工业界和监管机构来说都是一个独特的挑战，特别是在那些在临床试验中代表性不足的种族和民族群体中表现出特定人群频率的变体。尽管药物基因组学取得了重大进展，但这些 CYP2D6 罕见变体的底物特异性和相关临床相关性在很大程度上仍不清楚，需要进一步努力来描述这些变体对不良药物反应和药物疗效的负担。因此，可以使用基于细胞的体外系统来告知底物特异性影响和罕见变体的整体相关性。肝微粒体、基于细胞的表达系统、离体原代样本和纯化的变体蛋白都已与各种底物一起使用，以潜在地预测新底物的临床影响。在这篇综述中，我们确定了 CYP2D6 的罕见变体，这些变体在不同种族中的流行率存在差异，因此在临床试验中往往未被评估。因此，我们检查了目前用于以底物特异性方式分析这些罕见变体功能影响的药物基因组学体外模型。意义陈述：CYP2D6 的变体在药物代谢中具有临床相关作用，导致潜在的安全性和疗效问题。尽管常见变体的影响通常得到很好的描述，但罕见变体通常不包括在临床试验中。本综述通过突出分析 CYP2D6 底物代谢中罕见变体影响的体外模型，捕捉了 CYP2D6 罕见变体的临床相关性。
