Influences of CYP2D610 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis.

Aim: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D610 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients.

Methods: Seventy Chinese schizophrenia patients were enrolled, from whom limited blood samples were collected on d 15 (0 h) and d 28 (0, 4 and 12 h after drug administration). The plasma concentrations of iloperidone and its metabolites M (P-88) and M (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D610 (rs1065852) genotyping was performed. A PPK model was developed based on data from the patients using the NONMEM software (version 7.2). A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetic data related to iloperidone and its metabolites.

Results: Patients with the CYP2D610 T/T genotype had significantly higher concentrations of iloperidone and M, and lower concentrations of M than the patients with C/C or C/T genotypes. The CYP2D610 genotype affected the elimination constants for transformation of iloperidone to the metabolites M (K) and M (K). The K value of the patients with T/T genotype was 1.34-fold as great as that of the patients with C/C or C/T genotype. The K value of the patients with C/T and T/T genotypes was 0.693- and 0.492-fold, respectively, as low as that of the patients with C/C genotype.

Conclusion: CYP2D610 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D610 mutations need to be optimized.