Leveraging in Vitro Models for Clinically Relevant Rare CYP2D6 Variants in Pharmacogenomics.

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. CYP2D6 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 CYP2D6 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. Additionally, many rare variants have higher population-specific frequencies in racial and ethnic groups that are poorly represented in clinical trials, further impacting the ability to characterize their clinical relevance. Despite significant advancement in pharmacogenomics, the substrate specificity and related clinical relevance of these CYP2D6 rare variants remains largely unclear and further efforts are warranted to characterize the burden of these variants on adverse drug reactions and drug efficacy. In this review, we identify rare variants of CYP2D6 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 in CYP2D6 play a clinically relevant role in drug metabolism, leading to potential safety and efficacy concerns. While the influence of prevalent variants are often well-characterized, rare variants are traditionally not included in clinical trials. This review captures the clinical relevance of rare variants in CYP2D6 by highlighting in vitro models that analyze their impact on the metabolism of CYP2D6 substrates.