Pharmacokinetic Analysis For Iloperidone In Chinese Healthy Volunteers And Patients With Schizophrenia

OBJECTIVESStudy pharmacokinetic characteristic for iloperidone and its metabolites in Chinese healthy volunteers.Establish a population pharmacokinetics model for iloperidone in Chinese patients with schizophrenia for population parameters and investigate the factors affecting the population pharmacokinetics.Study the effects of CYP2D6*10(rs1065852) genotypes on pharmacokinetic parameters for iloperidone and its metabolites.METHODS16Chinese healthy volunteers were enrolled in the present randomized, two doses (lmg,3mg), two phases-cross study with14days washout periods followed by the inclusion/exclusion criteria. A series blood samples were collected before drug administration and at0.5,1,1.5,2,3,4,6,8,12,24,36,48,96and120h after drug administration. Plasma concentrations of iloperidone and metabolites (M1, M2) were detected by HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNolin software. Statistical analysis was performed with SPSS18.0software.70Chinese patients with schizophrenia followed by the inclusion/exclusion criteria were enrolled in PPK study with detailed basic information.Sparse blood samples were collected at15th day,28th day morning before and4,12hours after drug titration. Plasma concentrations of iloperidone and metabolites (M1, M2) were detected by HPLC-MS/MS method. Nonlinear mixed-effects modeling (NONMEN) method was used to develop a population pharmacokinetic model for iloperidone.Genomic DNA were purified from peripheral lymphocytes of Chinese volunteers (n=14) and patients with schizophrenia (n=70). CYP2D6*10(rs1065852) genotypes were detected by gene sequencing method. SPSS18.0was used for statistic analysis about genetic influences on plasma concentrations and pharmacokinetic parameters.RESULTSAfter a single oral administration of iloperidone tablets, pharmacokinetics of iloperidone and M1were fitted a two-compartment open model, while a one-compartment model for M2. Major pharmacokinetic parameters (Cmax, AUC and CL/F) of iloperidone were different significantly between doses and subjects. Dose proportional relationship for increased Cmax and AUC of iloperidone was not found. The frequency of adverse effects was higher than reports in healthy volunteers.A PPK model for iloperidone in patients with schizophrenia was established, and showed that CYP2D6*10(rs1065852) mutations affected K20and K24with individual differences decreased by1.8%and7%respectively. Red blood capsule in model affected volume of distribution of iloperidone with individual differences decreased by1.3%.Mutation frequencies of CYP2D6*10were21.4%and24.3%in healthy volunteers and patients respectively. The Concentration/Dose (C/D) ratio of M2in patients with CYP2D6*10TT group were lower, but C/D ratio of iloperidone and M1were higher than CT and CC groups. No statistical significant differences were existed between different genotype groups.CONCLUSIONSPharmacokinetic characters in Chinese healthy volunteers of iloperidone increased without dose proportional relationship with single dose of iloperidone tablet (lmg or3mg). Pharmacokinetic parameters and frequencies of adverse events were higher than studies in foreigners.Established PPK model of illoperiodone showed CYP2D6*10(rs1065852) mutations and red blood capsule decreased the individual differences on K20, K24and V2, and interpreted the individual differences on estimation and distribution of iloperidone partially. CYP2D6*10(rs1065852) mutations affected steady-state concentrations of iloperidone, M1and M2in patients with schizophrenia.