Abstract
Background. Risperidone, an antipsychotic agent which combines potent serotonin 5-HT2 and dopamine D2 receptor antagonism, is widely used in the treatment of schizophrenia and other psychiatric illnesses. Compared with tablets, extended-release risperidone microspheres have longer interval between dosing. Polymorphisms in genes encoding metabolic enzymes, receptors, and transporters may be associated with risperidone response. The aim of this study was to evaluate the impact of CYP2D6 genotypes, the allele distribution of which varied in Caucasians and Asians, on the pharmacokinetics and treatment effect of risperidone after injecting extended-release risperidone microspheres (LY03004) in Chinese subjects with schizophrenia.
Methods. 50 patient received 5 biweekly intramuscular injection of LY03004 at 25 mg. The polymorphic alleles of CYP2D6*4, CYP2D6*10, CYP2D6*14 were determined in each subjects. Positive and negative syndrome scale (PANSS) scores were collected in D0, D13, D27, D41, D55, D85 and D113.
Results. The CYP2D6*10 significantly influenced the AUC(0-D14) of risperidone after 1st injection. The AUC(0-D14) ratio of risperidone(R)/ 9-hydroxy risperidone(9-OHR) were significantly increased from CYP2D6*1/*1 to CYP2D6*10/*10 with for CYP2D6*10/*10 being 2.5-fold higher for CYP2D6*1/*1 (0.485, 1.04, 1.71 for the CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10, respectively, P=0.000). Following repeated doses of LY03004, the plasma concentrations of risperidone significantly elevated in the CYP2D6*10/*10 compared with CYP2D6*1/*1 with P=0.006 for C(max,ss) and P=0.001 for AUC(0-tau,ss). The plasma concentrations of 9-OHR appeared to be slightly declined in the CYP2D6*10/*10 compared with CYP2D6*1/*1, with 9-OHR C(max,ss) also showing statistically significance (P=0.047). No significant difference was found in pharmacokinetic parameters of active moiety (AM). There was a trend of decline in total PANSS score, while it showed no significant difference between different genotypes. No mutant genotype was found in CYP2D6*4 or CYP2D6*14.
Conclusion CYP2D6*10 could affect the Cmax and AUC of risperidone and risperidone/9-hydroxy risperidone, but the decreased enzyme activity is not sufficient to affect AM. Also, current results did not show that CYP2D6*10 could affect the treatment effect of risperidone.
