Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

Abstract

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.

Introduction of new alternative pipeline using multiplexed fast COLD‑PCR together with sequencing approach highlighting pharmacoeconomics by detection of CYP variants

“…In previous studies, frequencies of only 0.08% for CYP2C9*2 , 25.6% for CYP2C19*2 and 2.5% for CYP2C19*3 alleles were found in a Thai population ( 26 , 41 ). For CYP2D6 in Thai population, the decreased-function allele CYP2D6*10 is the most common allele found in patients treated with risperidone, at 51.8%, followed by CYP2D6*41 at 6.8% ( 42 ). Although the present allele representation frequency was higher than previous studies ( 26 , 41 , 42 ), it may be due to small sample size.…”

“…For CYP2D6 in Thai population, the decreased-function allele CYP2D6*10 is the most common allele found in patients treated with risperidone, at 51.8%, followed by CYP2D6*41 at 6.8% ( 42 ). Although the present allele representation frequency was higher than previous studies ( 26 , 41 , 42 ), it may be due to small sample size. Nevertheless, the present COLD-PCR results showed 100% agreement with Sanger sequencing results.…”

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications

“…Risperidone was approved in 2006 by the FDA at a typical dose of 1–3 mg/day. In 2009, aripiprazole was ratified by the FDA at a typical dose of up to 15 mg/day ( Riesgo, R., Gottfried, C., & Becker, 2013 ; Lord et al, 2018 ; DeVane et al, 2019 ; Hongkaew et al, 2021b ; Biswas et al, 2022b ).…”

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

“…Additional literature available 5 years later, however, supported assigning a value of 0.25, instead of the original value of 0.5, to more accurately reflect the significantly decreased activity across substrates of the CYP2D6*10 allele 1 . This move indeed improves phenotype prediction, as demonstrated in a Thai population with a high frequency of CYP2D6*10 alleles using risperidone metabolic ratios 4 . The working group also identified other alleles, namely CYP2D6*9 , *17 , *29 , and *41 , that would merit from being systematically re‐evaluated.…”

“…1 This move indeed improves phenotype prediction, as demonstrated in a Thai population with a high frequency of CYP2D6*10 alleles using risperidone metabolic ratios. 4 The working group also identified other alleles, namely CYP2D6*9, *17, *29, and *41, that would merit from being systematically re-evaluated.…”