A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status

Abstract

Aims: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight. Methods: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993–2017. Results: There were 17 787 measurements from 5960 patients (4315 male) aged 18–86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h−1 between 20 and 80 years. Model-based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L−1 was 275 (90% prediction interval 125, 625) mg day−1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years. Conclusion: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L−1. The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.