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CYP2D6 Genotype-Based Dose Recommendations for Risperidone in Asian People.

ABSTRACT: The aim of this study was to provide dose recommendations for risperidone in Asian people based on cytochrome P450 enzyme CYP2D6 genotype. First, we investigated the influence of CYP2D6 polymorphism on the pharmacokinetics of risperidone in Chinese patients with schizophrenia. Then, we performed a search for studies covering the relationship between pharmacokinetic parameters of risperidone and CYP2D6 genotype. Pooled pharmacokinetic parameters were meta-analyzed using a random-effects model. Lastly, we calculated the dose adjustment for risperidone based on CYP2D6 genotype for white and Asian people. Significant differences between the extensive metabolizer and intermediate metabolizer groups were observed for dose-adjusted risperidone level, 9-hydroxyrisperidone level, and risperidone/9-hydroxyrisperidone ratio, but not for the total active moiety. Meta-analysis showed that significant differences were observed among the four phenotype groups, including steady state concentration, peak risperidone concentration, and the area under the curve, using the Kruskal-Wallis test. No differences were found in oral clearance. For risperidone, dose recommendations for poor and ultrarapid metabolizers of CYP2D6 for Asians were different compared to that for white people for poor metabolizers (dose adjustment around 45% for white people, while for Asians the risperidone dose should be reduced by 26%). For ultrarapid metabolizers, risperidone dose should be increased by about 33% for white people and 30% for Asians. This was a first attempt to apply pharmacogenetics to suggest dose-regimens for Asian people; further research to replicate and extend these findings is recommended.

SUBMITTER: Cui Y

PROVIDER: S-EPMC7417932 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CYP2D6 Genotype-Based Dose Recommendations for Risperidone in Asian People.

Cui Yuanxia Y Yan Hao H Su Yi Y Wang Lifang L Lu Tianlan T Zhang Dai D Yue Weihua W

Frontiers in pharmacology 20200804

The aim of this study was to provide dose recommendations for risperidone in Asian people based on cytochrome P450 enzyme CYP2D6 genotype. First, we investigated the influence of CYP2D6 polymorphism on the pharmacokinetics of risperidone in Chinese patients with schizophrenia. Then, we performed a search for studies covering the relationship between pharmacokinetic parameters of risperidone and CYP2D6 genotype. Pooled pharmacokinetic parameters were meta-analyzed using a ran ...[more]

PMID: 32848719

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Project 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.

Project description:BackgroundThis study aimed to investigate the influence of CYP2D6 polymorphisms on risperidone plasma concentrations in patients with schizophrenia. Based on pharmacogenomics, we examined whether plasma concentration of risperidone is associated with clinical response and adverse side-effects.MethodsWe recruited patients with chronic schizophrenia who were then treated with risperidone. The CYP2D6 genotypes were determined using targeted sequencing. All high-frequency mutation sites of the nine exons of the gene were assayed in the present study. Plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-RIS) were measured using high-performance liquid chromatography (HPLC). Psychiatric symptoms were monitored using The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Adverse effects were evaluated using the Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS). Follow-up visits were scheduled at weeks 2,4, and 8 after treatment initiation.ResultsAmong the 76 patients, 100 C > T (rs1065852), 1038 C > T (rs1081003), 1662 G > C (rs1058164), 2851 C > T (rs16947), and 4181G > C (rs1135840) variants were detected. The most common allele was CYP2D6*10 (81.6%), whereas CYP2D6*2 (9.2%) and CYP2D6*5 (17.1%) were relatively rare. Plasma levels of risperidone and the risperidone/9-OH risperidone ratio (R/9-OH) were significantly increased in individuals with CYP2D6*10 (P < 0.05). The change in PANSS score, weight, high-density lipoprotein (HDL) level, prolactin (PRL) level, and ESRS were significantly different from baseline, between the different genotypes (P < 0.01). Moreover, individuals with CYP2D6*10 homozygous (TT) mutations were associated with higher risperidone concentration and R/9-OH ratio than those with heterozygous mutations (CT) (P < 0.01). A change from baseline in BPRS scores was observed only during week 8 and was different between heterozygous and homozygous mutations. As for the C2851T polymorphism, the incidence of adverse metabolic effects was significantly different between the C/C and C/T genotypes (P < 0.01). Regarding the G4181C polymorphisms, the changes from baseline in GLU and TG, were different between the C/C and C/G genotypes (P < 0.01).ConclusionsThe genotype of CYP2D6 significantly influences the plasma concentration of risperidone and may subsequently influence the adverse side-effects following risperidone treatment, while also exerting a slight influence on clinical outcomes.

Dataset Information

CYP2D6 Genotype-Based Dose Recommendations for Risperidone in Asian People.

Publications

<i>CYP2D6</i> Genotype-Based Dose Recommendations for Risperidone in Asian People.

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