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 Ndesmethylclozapine (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 to 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 pre-dose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in a nonsmoking White male 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 age 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 a pre-dose plasma clozapine concentration of 0.35 mg L-1. The analysis was however limited by the absence of data on clinical outcome and further studies
are required to determine optimal pre-dose concentrations specifically in those aged over 65 years
