Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia.

AIM: To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters. METHODS: Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors. RESULTS: A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients. CONCLUSION: Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

[The application of evaluation tools for criminal responsibility in forensic psychiatric expertise].

Criminal responsibility is divided into three types: full criminal responsibility, diminished criminal responsibility and criminal irresponsibility in China. In forensic psychiatric expertise, doctors often have different opinions about the responsibility in a given case because of lacking objective criteria. The evaluation of criminal responsibility is always unresolved problem in forensic psychiatric expertise. Application of these evaluation tools in forensic psychiatric expertise were reviewed in this article. The value of the tools were still controversial in the reliability and validity, but it is clear that these tools have the positive roles in ensuring the standardization and the uniformity of the forensic investigation.

[Population pharmacokinetics research of clozapine in Chinese schizophrenic patients].

The goal of this study is to investigate the population pharmacokinetics of oral given clozapine in Chinese schizophrenic patients and to identify possible relationships between population parameters and covariates including demography factors and CYP1A2 genetic polymorphism, so as to create the population pharmacokinetics model to guide individual clinical delivery. Details of drug dosage history, sampling time and concentration of 626 data points from 183 patients were collected retrospectively. The 183 patients were randomly allocated either to the index group (n = 168) or to the validation group (n = 15). Population pharmacokinetic data analysis was performed using the nonlinear mixed-effects model (NONMEM) program on the index group. The values of apparent clearance (CL/F), apparent volume of distribution (V/F) and the constant of absorption rate were estimated. A number of covariates including demographic index, coadministration of other drugs and CYP1A2 genotypes were evaluated statistically for their influence on these parameters. The final population model related clearance with day-dose/BSA (DBSA) and smoke habit (SMOK). Predictive performance of the final model evaluated with the validation group showed insignificant bias between observed and model predicted concentrations. Typical value of CL/F (non-smoking group), V/F and the constant of absorption rate were 28.5 L x h(-1) (5.05%), 1 290 L (16.7%) and 2.26 h(-1) (fixed), inter-patient variability (CV) in CL/F and V/F was) 42.2% and 10.0%, respectively. It was observed that the values of CL/F in the two smoking groups were higher than that in the non-smoking group. The residual variability (SD) between observed and model-predicted concentrations was 45.8 microg x L(-1).