Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of
CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the
CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for
CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between
CYP2D6 genotype and
risperidone measures. One hundred and ninety-nine children and adolescents with
autism treated with a
risperidone-based regimen for at least four weeks were included.
CYP2D6 genotype was determined using the Luminex xTAG
CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of
risperidone and
9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of
risperidone,
risperidone concentration/dose ratio, and
risperidone/
9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma
risperidone levels and
risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25-0.75) than normal metabolizer (defined as AS = 1-2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as
risperidone/
9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the
CYP2D6 genotype to phenotype. In addition to validating that
CYP2D6 genetic variation significantly impacts
risperidone metabolism, we demonstrated that revised value for the
CYP2D6*10 was superior for genotype to phenotype translation. However, at least for
risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.