CYP2D6*9 and *41: Does the Activity Value Assigned to these Alleles Need to be Reduced to more Accurately Predict Phenotype?

Abstract

The article published by Jukić et al. used a large dataset comprising 4,700 patients to calculate metabolic ratios of 3 CYP2D6-metabolized drugs across eleven CYP2D6 diplotypes. The observed ratios suggest that the values assigned to the CYP2D6*9 and *41 decreased function alleles to calculate the Activity Score (AS) should be re-evaluated to improve phenotype prediction from genotype data. Of note, metabolic ratios (serving as surrogate measures of CYP2D6 activity) were similar across aripiprazole, risperidone, and venlafaxine.

Using population pharmacokinetic analyses of drugs metabolized by CYP2D6 to study the genotype–phenotype translation

“…The process to reach consensus and implement changes to existing guidelines and activity values may be rigorous and lengthy. This is evident from the 2019 consensus report by CPIC/DPWG on CYP2D6 genotype–phenotype translation, requiring more than eight surveys in a process lasting more than a year 13,14 . Another challenge is that it is difficult to generate robust evidence to support the functional assignment of CYP2D6 alleles and genotypes.…”

“…It is widely accepted that CYP2D6 phenotype can be used to identify individuals at risk of suboptimal treatment outcomes and several drug labels, and treatment guidelines provide recommendations for CYP2D6 ‐guided drug therapy 5–11 . However, the process of translating CYP2D6 genotype information into phenotype categories has historically suffered from a lack of consensus and continues to be debated 12–15 …”

“…[5][6][7][8][9][10][11] However, the process of translating CYP2D6 genotype information into phenotype categories has historically suffered from a lack of consensus and continues to be debated. [12][13][14][15] In 2008, the activity score (AS) system was introduced with the intention to facilitate CYP2D6 genotypephenotype translation. 16 The AS system assigns a value to each allele reflecting the enzyme activity relative to the wild-type (CYP2D6*1): null function alleles (e.g., CYP2D6*3, *4, *5 and *6) are assigned a value of 0, decreased function alleles are assigned a value of either 0.25 (CYP2D6*10) or 0.5 (e.g., CYP2D6*9, *17, *29 and *41) and normal function alleles (e.g.…”