Does ethnicity impact CYP2D6 genotype-phenotype relationships?

Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N = 476), (ii) tedatioxetine (N = 500), and (iii) vortioxetine (N = 1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans. The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes.