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...
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2021-02-01
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doaj-ebf0c9230abb4e119004cb08ef98e00d2021-02-21T12:35:45ZengNature Publishing GroupScientific Reports2045-23222021-02-011111810.1038/s41598-021-83570-wRelationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidoneYaowaluck Hongkaew0Andrea Gaedigk1Bob Wilffert2Nattawat Ngamsamut3Wiranpat Kittitharaphan4Penkhae Limsila5Chonlaphat Sukasem6Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol UniversityDivision of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Kansas CityUnit of PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of GroningenYuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public HealthYuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public HealthYuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public HealthDivision of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol UniversityAbstract 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.https://doi.org/10.1038/s41598-021-83570-w |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yaowaluck Hongkaew Andrea Gaedigk Bob Wilffert Nattawat Ngamsamut Wiranpat Kittitharaphan Penkhae Limsila Chonlaphat Sukasem |
spellingShingle |
Yaowaluck Hongkaew Andrea Gaedigk Bob Wilffert Nattawat Ngamsamut Wiranpat Kittitharaphan Penkhae Limsila Chonlaphat Sukasem Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone Scientific Reports |
author_facet |
Yaowaluck Hongkaew Andrea Gaedigk Bob Wilffert Nattawat Ngamsamut Wiranpat Kittitharaphan Penkhae Limsila Chonlaphat Sukasem |
author_sort |
Yaowaluck Hongkaew |
title |
Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone |
title_short |
Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone |
title_full |
Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone |
title_fullStr |
Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone |
title_full_unstemmed |
Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone |
title_sort |
relationship between cyp2d6 genotype, activity score and phenotype in a pediatric thai population treated with risperidone |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-02-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-021-83570-w |
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