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

Abstract

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.

Figure 1

Population pharmacokinetic model structure for clozapine and norclozapine. K₂₀, elimination rate constant for clozapine; V, volume of distribution for clozapine; K₂₃, rate constant for the conversion of clozapine into norclozapine; K₃₀, elimination rate constant for norclozapine; V_M, volume of distribution for norclozapine; KF, fraction of clozapine converted into norclozapine.

Figure 2

Diagnostic plots for the final pharmacokinetic model. Plot of the observed concentrations vs the population-predicted clozapine (A) and norclozapine (E) concentrations. Plot of the observed concentrations vs the individual population-predicted clozapine (B) and norclozapine (F) concentrations. Plot of the conditional weighted residual error (CWRES) vs the population-predicted clozapine (C) and norclozapine (G) concentrations. Plot of the conditional weighted residual error (CWRES) vs the time after first dose of clozapine (D) and norclozapine (H).

Figure 3

Boxplot with the median and interquartile range of the clearance of clozapine and norclozapine according to sex and smoking status. Clozapine clearance in female nonsmokers, male nonsmokers and male smokers (A). Norclozapine clearance in female nonsmokers, male nonsmokers, and male smokers (B).

Figure 4

Results of the NPDE analysis for clozapine (A) and norclozapine (B). The left upper plot is a QQ-plot for NPDE; the right upper plot is a histogram of the NPDE; the left lower and right lower plots represent the NPDE versus time and the NPDE versus the predicted concentrations of clozapine or norclozapine, respectively.