Abstract
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 CYP2D6*10 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 M1 (P-88) and M2 (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D6*10 (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 CYP2D6*10 T/T genotype had significantly higher concentrations of iloperidone and M1, and lower concentrations of M2 than the patients with C/C or C/T genotypes. The CYP2D6*10 genotype affected the elimination constants for transformation of iloperidone to the metabolites M1 (K23) and M2 (K24). The K23 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 K24 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:
CYP2D6*10 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D6*10 mutations need to be optimized.
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Acknowledgements
The authors wish to thank the investigators from the 13 hospitals led by the 6th Hospital of Peking University in China for collecting the samples and the data. The authors would also like to thank the co-investigators from the Jilin University Drug Metabolism Research Center for data analysis. This study was supported by grants from the International Science & Technology Cooperation Program of China (No 2014DFA30900), the National Key Clinical Specialist Construction Programs of China, the National Natural Science Foundation of China (No 81302851, 81373476, 81301924), the State Scholarship Fund (No 201308430123), the Health Department Foundation of Hunan Province (No 132013-028) and the Program for Science and Technology Research of Hunan Province (No 2012WK3044).
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Pei, Q., Huang, L., Huang, J. et al. Influences of CYP2D6*10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis. Acta Pharmacol Sin 37, 1499–1508 (2016). https://doi.org/10.1038/aps.2016.96
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DOI: https://doi.org/10.1038/aps.2016.96
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