Influences of CYP2D6*10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis.
OBJECTIVE
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 M2than 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 K23value 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 K24value 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.


CONCLUSIONS
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.
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Qi
Q
Pei
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Lu
L
Huang
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Jie
J
Huang
Drug Metabolism Research Center of Jilin University, Changchun 130012, China.
Jing-Kai
JK
Gu
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Yun
Y
Kuang
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Xiao-Cong
XC
Zuo
Children's Hospital of Fudan University, Shanghai 200032, China.
Jun-Jie
JJ
Ding
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Hong-Yi
HY
Tan
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Cheng-Xian
CX
Guo
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Shi-Kun
SK
Liu
Center of Clinical Pharmacology and Pharmacy Department, Third Xiangya Hospital, Central South University, Changsha 410013, China.
Guo-Ping
GP
Yang
D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D044466:Asian People; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010880:Piperidines / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D014150:Antipsychotic Agents; D007555:Isoxazoles; D010880:Piperidines; D019389:Cytochrome P-450 CYP2D6; C081732:iloperidone
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