Cargando…

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

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 substanti...

Descripción completa

Detalles Bibliográficos
Autores principales: Hongkaew, Yaowaluck, Gaedigk, Andrea, Wilffert, Bob, Ngamsamut, Nattawat, Kittitharaphan, Wiranpat, Limsila, Penkhae, Sukasem, Chonlaphat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892547/
https://www.ncbi.nlm.nih.gov/pubmed/33603025
http://dx.doi.org/10.1038/s41598-021-83570-w
_version_ 1783652869621153792
author Hongkaew, Yaowaluck
Gaedigk, Andrea
Wilffert, Bob
Ngamsamut, Nattawat
Kittitharaphan, Wiranpat
Limsila, Penkhae
Sukasem, Chonlaphat
author_facet Hongkaew, Yaowaluck
Gaedigk, Andrea
Wilffert, Bob
Ngamsamut, Nattawat
Kittitharaphan, Wiranpat
Limsila, Penkhae
Sukasem, Chonlaphat
author_sort Hongkaew, Yaowaluck
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7892547
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-78925472021-02-22 Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone Hongkaew, Yaowaluck Gaedigk, Andrea Wilffert, Bob Ngamsamut, Nattawat Kittitharaphan, Wiranpat Limsila, Penkhae Sukasem, Chonlaphat Sci Rep Article 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. Nature Publishing Group UK 2021-02-18 /pmc/articles/PMC7892547/ /pubmed/33603025 http://dx.doi.org/10.1038/s41598-021-83570-w Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hongkaew, Yaowaluck
Gaedigk, Andrea
Wilffert, Bob
Ngamsamut, Nattawat
Kittitharaphan, Wiranpat
Limsila, Penkhae
Sukasem, Chonlaphat
Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892547/
https://www.ncbi.nlm.nih.gov/pubmed/33603025
http://dx.doi.org/10.1038/s41598-021-83570-w
work_keys_str_mv AT hongkaewyaowaluck relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone
AT gaedigkandrea relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone
AT wilffertbob relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone
AT ngamsamutnattawat relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone
AT kittitharaphanwiranpat relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone
AT limsilapenkhae relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone
AT sukasemchonlaphat relationshipbetweencyp2d6genotypeactivityscoreandphenotypeinapediatricthaipopulationtreatedwithrisperidone