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

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.

Assessing Adherence to Clozapine

“…22 Model-based estimates from TDM data gave the half-lives of clozapine and of norclozapine as 36 and 69 hours, respectively (White European male, nonsmoker, 40 years, 70 kg). 23 The half-life of clozapine is shorter in smokers, in younger people, and in people of Afro-Caribbean ancestry, and longer in women, in older people, and in people of South Asian ancestry. Other factors, including diet, polymorphisms in genes coding for CYP450 enzymes, the presence of clozapine-induced gastrointestinal hypomotility, and certain coadministered drugs may also affect clozapine pharmacokinetics in individual patients.…”

“…The plasma half-life of clozapine has been reported as 9 to 17 hours, 21 but this increases after repeat dosing 22 . Model-based estimates from TDM data gave the half-lives of clozapine and of norclozapine as 36 and 69 hours, respectively (White European male, nonsmoker, 40 years, 70 kg) 23 . The half-life of clozapine is shorter in smokers, in younger people, and in people of Afro-Caribbean ancestry, and longer in women, in older people, and in people of South Asian ancestry.…”

Will ChatGPT3 Substitute for us as Clozapine Experts?

“…An olanzapine population pharmacokinetic model using the plasma olanzapine concentrations from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) 15 demonstrated that African-Americans need higher doses (1.3 times higher) than Whites to reach the same olanzapine concentrations. The predicted need for higher clozapine concentrations in patients of African ancestry 16 to reach the minimum therapeutic dose had been verified by a population pharmacokinetic study from the United Kingdom that was published electronically on February 15, 2023 17 …”

“…The predicted need for higher clozapine concentrations in patients of African ancestry 16 to reach the minimum therapeutic dose had been verified by a population pharmacokinetic study from the United Kingdom that was published electronically on February 15, 2023. 17…”

A Systematic Review of Clozapine Concentration–Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders

“…Patients of Asian (of ancestries ranging from Pakistan to Japan) or American ancestry (indigenous or native Americans) require the lowest clozapine doses, whereas those of European ancestry require intermediate doses and those of African ancestry require the highest doses. 27,28 In adults with schizophrenia, the average minimum therapeutic dose required to reach a plasma or serum concentration of 350 ng/mL was used to compare individuals and groups based on clozapine clearance. The minimum therapeutic dose ranges are as follows: (1) 166 mg/d (nonsmoker women) to 270 mg/d (smoker men) in patients of Asian (or American) ancestry, (2) 236-368 mg/d in patients of European ancestry, (3) and 300-600 mg/d in patients of African ancestry (based on US recommended doses).…”