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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Autores principales:	Yaowaluck Hongkaew, Andrea Gaedigk, Bob Wilffert, Nattawat Ngamsamut, Wiranpat Kittitharaphan, Penkhae Limsila, Chonlaphat Sukasem
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Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ebf0c9230abb4e119004cb08ef98e00d
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spelling	oai:doaj.org-article:ebf0c9230abb4e119004cb08ef98e00d2021-12-02T10:54:31ZRelationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone10.1038/s41598-021-83570-w2045-2322https://doaj.org/article/ebf0c9230abb4e119004cb08ef98e00d2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83570-whttps://doaj.org/toc/2045-2322Abstract 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 CYP2D610 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 CYP2D610 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.Yaowaluck HongkaewAndrea GaedigkBob WilffertNattawat NgamsamutWiranpat KittitharaphanPenkhae LimsilaChonlaphat SukasemNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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 CYP2D610 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 CYP2D610 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.
format	article
author	Yaowaluck Hongkaew Andrea Gaedigk Bob Wilffert Nattawat Ngamsamut Wiranpat Kittitharaphan Penkhae Limsila Chonlaphat Sukasem
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 Portfolio
publishDate	2021
url	https://doaj.org/article/ebf0c9230abb4e119004cb08ef98e00d
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Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

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