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.
Highlights
Risperidone (RIS) is an atypical antipsychotic (AAP) drug that is prescribed for the treatment of autism, schizophrenia, and acute bipolar mania, which is metabolized by the CYP2D6 enzyme in the liver to its major active metabolite, 9-hydroxyrisperidone (9-OH-RIS, known as paliperidone)
Phenotype extrapolation from CYP2D6 genotype resulted in 71 (54.6%) and 59 (45.4%) patients classified into the normal metabolizers (NM) and intermediate metabolizers (IM) groups, respectively
Risperidone is an active compound that is mainly metabolized in the liver by cytochrome P450 enzymes such as CYP2D6
Summary
Risperidone (RIS) is an atypical antipsychotic (AAP) drug that is prescribed for the treatment of autism, schizophrenia, and acute bipolar mania, which is metabolized by the CYP2D6 enzyme in the liver to its major active metabolite, 9-hydroxyrisperidone (9-OH-RIS, known as paliperidone). Dose Recommendation for Risperidone rise to four different metabolizer phenotypes (enzyme activity levels) based on the sum of an activity score that is attributed to each allele including: (1) poor metabolizers (PM) without enzyme activity (activity score 0); (2) intermediate metabolizers (IM) with reduced enzyme activity (activity score 0–1.25); (3) normal metabolizers (NM) with normal activity (activity score 1.25–2.25); and (4) ultrarapid metabolizers (UM) with increased enzyme activity (activity score >2.25) (Caudle et al, 2020). The plasma concentration of risperidone may range from subtherapeutic levels in the UM group to supratherapeutic and potentially toxic concentrations in the PM group, thereby (if RIS and 9-OH-RIS differ in adverse effect profile) potentially increasing the possibility of adverse effects. The plasma concentration of risperidone and the risperidone/9-hydroxyrisperidone ratio in patients varied by CYP2D6 predicted phenotype group, suggesting that the determination of an accurate CYP2D6 genotype-predicted phenotype may be helpful for the individualization of drug therapy in a clinical setting (van der Weide and van der Weide, 2015; Vanwong et al, 2016)
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