Affiliation:
1. Division of Psychiatry University College London London UK
2. Institute of Genetics University College London London UK
3. UMR 1137 Infection, Antimicrobials, Modelling, Evolution (IAME) French Institute for Medical Research (INSERM) University of Paris Paris France
4. Precision Medicine, Networked Services, Bessemer Wing King's College Hospital NHS Foundation Trust London UK
Abstract
AimsGuidance 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.MethodsA 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.ResultsThere 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.ConclusionThe 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.
Funder
UCLH Biomedical Research Centre
Subject
Pharmacology (medical),Pharmacology
Cited by
15 articles.
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