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

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 M 1 (P-88) and M 2 (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 M 1 , and lower concentrations of M 2 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 M 1 (K 23 ) and M 2 (K 24 ). The K 23 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 24 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.

Comparison of adverse drug reactions between tamoxifen and toremifene in breast cancer patients with different CYP2D6 genotypes: A propensity‐score matched cohort study

“…However, CYP2D6*10 (48%-70%) was the most common CYP2D6 polymorphism in Chinese. 50 The decreased functional allele CYP2D6*41 and the nonfunctional alleles CYP2D6*4 and *5 occur respectively in only 3.2%, 0.2% and 1.7% of the Chinese population, which might have little influence on our results. 51 Furthermore, it is not recommended in the CPIC guideline that rare variants must be detected for CYP2D6 genotyping.…”

Evaluation of the Relationship Between Cytochrome P450 Polymorphisms and T2DM Risk

“…Previous study suggested that rs1065852 was a favorable factor in escitalopram treatment for major depressive disorder [30]. The mutation rs1065852 affects the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients [31]. The SNP rs1065852 was found to be associated with increased risk of lung cancer in the Northwestern Chinese Han population [24].…”

Genetic polymorphisms of pharmacogenomic VIP variants in Chinese Lisu population

“…CYP2D6 substrates are also the rst-line medications in psychiatry, scholars [22] have proposed it before that the CYP2D6 genotype has a great in uence on the blood concentration of aripiprazole, while the CYP3A genotypes and CYP3A4 expression have a small or even negligible effect on aripiprazole clearance. Iloperidone elimination was detected to be expressively impacted by the CYP2D6 rs1065852 variants [23]. Hence, the mutation of CYP2D6 gene may lead to poisoning or no response under normal dose of drugs, which affects the treatment outcomes and costs [24].…”

“…(3) Southern Han Chinese, China (CHS), (4) Japanese in Tokyo, Japan (JPT), (5) Kinh in Ho Chi Minh City, Vietnam (KHV), (6) African Caribbeans in Barbados (ACB), (7) African ancestry in the southwestern USA (ASW), (8) Esan in Nigeria (ESN), (9) Gambian in Western Divisions, The Gambia (GWD), (10) Luhya in Webuye, Kenya (LWK), (11) Mende in Sierra Leone (MSL), (12) Yoruba in Ibadan, Nigeria (YRI), (13) Colombian in Medellin, Colombia (CLM), (14) Mexican Ancestry in Los Angeles, Colombia (MXL), (15) Peruvian in Lima, Peru (PEL), (16) Puerto Rican in Puerto Rico (PUR), (17) Utah residents with Northern and Western European ancestry (CEU), (18) Finnish in Finland (FIN), (19) British in England and Scotland (GBR), (20) Iberian populations in Spain (IBS), (21) Toscani in Italy (TSI), (22) Bengali in Bangladesh (BEB), (23) Gujarati Indian in Houston, Texas (GIH), (24) Indian Telugu in the UK (ITU), (25) Punjabi in Lahore, Pakistan (PJL), and (26) Sri Lankan Tamil in the UK (STU). Data mentioned above were all from the 1000 Genomes Project( http://www.1000genomes.org/).…”