Clozapine Exposure and the Impact of Smoking and Gender: A Population Pharmacokinetic Study

Abstract

The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean +/- SD age, 38 +/- 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg.The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine, smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form.The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring.

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

“…We built a combined structural model to explain the conversion of clozapine into norclozapine (Figure 1) based on the metabolism of clozapine. Therefore, in the current study, we assumed that clozapine was partly converted into norclozapine with a conversion fraction (KF), which was more reasonable than the assumption in previous PPK studies with respect to the process of clozapine metabolism [11,15,29] . The model proposed in this study provided an adequate fit to the data for both clozapine and norclozapine.…”

“…It was reported that smoking can increase the clearance of clozapine and that the sudden cessation of smoking can cause a significant decrease in caffeine clearance (P<0.01) of 36.1% [32][33][34] . Sex was also reported to be a significant covariate affecting the clearance of clozapine and norclozapine [11,35,36] . Previous studies have shown that CYP1A2 activity was lower in females than in males [37] , whereas other studies found no differences in CYP1A2 activity between males and females and insisted that smoking could induce CYP1A2 activity and reduce clozapine clearance [33,38] .…”

“…Significant intra-and inter-individual pharmacokinetic (PK) variability for clozapine and norclozapine has been observed in routine TDM [8,9] . The influences of sex, smoking, CYP1A2 activity and other factors on clozapine plasma concentrations have been previously reported [10][11][12][13] . However, studies exploring the effect of sex and smoking status on dose and concentration have shown mixed effects, and the clinical administration of clozapine is characterized by frequent dose changes and different dose intervals.…”

“…A review of the recent literature yielded two studies by one group on the PPK analysis of clozapine and norclozapine simultaneously. Robert R BIES et al developed a combined PPK model of clozapine and norclozapine for American patients based on the assumption that all clozapine was excreted as norclozapine, and they estimated the PK parameters using a fixed central volume of 7 L/kg for both clozapine and norclozapine [11,15] using retrospective TDM data and outpatient concentration data.…”

A Tipping Point in Drug Dosing in Late-Life Schizophrenia

“…Although some published studies support an age effect on plasma antipsychotic levels, this has not been a consistent finding [46•,47,48]. For example, we conducted a population pharmacokinetic study to evaluate the effects of age on oral clearance of clozapine and norclozapine, using a total of 519 plasma clozapine concentrations from 197 patients that were collected through routine therapeutic drug monitoring [48]. Our data demonstrated that while smoking and male sex were associated with increased oral clearance, age did not have any impact on the clearance of clozapine or norclozapine.…”