NextDose: A web-based Bayesian dose forecasting tool

Last updated 30 December 2024

Clozapine

Clozapine is used to treat schizophrenia and other psychotic disorders.

A population PK analysis of clozapine and norclozapine in a large group of patients (4315 men, 1645 women) was published in 2024 (Reeves, Bertrand et al. 2024). The model describes input with first-order absorption without lag time, distribution is to a single compartment with first-order metabolism to norclozapine and first-order elimination by an unidentified pathway. The model assumes the volume of distribution of clozapine (including between subject variability) is the same for norclozapine. This assumption allowed the clearance of clozapine by the unidentified pathway to be distinguished from metabolism to norclozapine (parameterized by a rate constant). Covariates included body size based on total body mass, age, sex (male, female), cigarette smoker (no,yes) and ethnicity (Caucasian, Asian, Afro-Caribbean). The median weight of patients was 87 kg in men and 80 kg in women.

A population PK model for clozapine alone was published subsequently based on a smaller group of 127 patients (Berneri, Jha et al. 2024). The model describes input with first-order absorption with lag time, distribution is to a single compartment with first-order by an unidentified pathway. Covariates included body size based on total body mass, sex (male, female), cigarette smoker (no,yes) and use of fluvoxamine (no,yes). The average weight of patients was 90.2 kg (men and women combined).

The dispersion of total body mass in both studies was quite large suggesting a wide variation in body composition. A weakness of both models was the use of total body mass without accounting for body composition using normal fat mass(Holford and Anderson 2017). Accounting for body composition is more physiological and could have accounted for the sex and ethnic differences associated with clozapine clearance.

In the absence of estimates of the influence of body composition on allometric size, the NextDose models account for differences in body size using theory based allometry and total body mass for both clearance and volume of distribution. They also accounts for maturation of clearance in neonates and infants using the maturation function described for glomerular filtration rate (Rhodin, Anderson et al. 2009).

The target concentration is for clozapine.

Three models are provided in NextDose.

1. Reeves 2024: The model is based on (Reeves, Bertrand et al. 2024). It is parameterized in terms of two clearance components. The clearance of clozapine to norclozapine is obtained by multiplying the clozapine volume of distribution by the rate constant for metabolism from clozapine to norclozapine. Observations of clozapine and norclozapine may be used to estimate individual PK parameters.

2. Berneri 2024: The model is based on (Berneri, Jha et al. 2024). It is parameterized in terms of a single clearance component for clozapine. The norclozapine concentration is predicted to be zero. Observations of clozapine may be used to estimate individual PK parameters.

3. Berneri 2024 & Reeves 2024: The clozapine component of the model is the same as Berneri 2024 but the model is extended to predict norclozapine concentrations. This assumes that the Berneri clozapine volume of distribution is the same for norclozapine and the Reeves estimate of the clozapine to norclozapine metabolism rate constant is suitable. Observations of clozapine and norclozapine may be used to estimate individual PK parameters.

Target Concentration

The target concentration for clozapine has not been clearly established. A target of 0.45 mg/L is suggested. This is based on the threshold for a favourable clinical response of 0.407 mg/L (Tralongo, Konecki et al. 2023) and a “therapeutic reference range” of 0.35 – 0.6 mg/L (Hiemke, Bergemann et al. 2018).

Berneri, M., U. Jha, S. O'Halloran, S. Salman, S. Wickramasinghe, K. Kendrick, J. Nguyen and D. A. Joyce (2024). "Validation of Population Pharmacokinetic Models for Clozapine Dosage Prediction." Ther Drug Monit 46(2): 217-226.

Hiemke, C., N. Bergemann, H. W. Clement, A. Conca, J. Deckert, K. Domschke, G. Eckermann, K. Egberts, M. Gerlach, C. Greiner, G. Gründer, E. Haen, U. Havemann-Reinecke, G. Hefner, R. Helmer, G. Janssen, E. Jaquenoud, G. Laux, T. Messer, R. Mössner, M. J. Müller, M. Paulzen, B. Pfuhlmann, P. Riederer, A. Saria, B. Schoppek, G. Schoretsanitis, M. Schwarz, M. S. Gracia, B. Stegmann, W. Steimer, J. C. Stingl, M. Uhr, S. Ulrich, S. Unterecker, R. Waschgler, G. Zernig, G. Zurek and P. Baumann (2018). "Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017." Pharmacopsychiatry 51(1-02): 9-62.

Holford, N. H. G. and B. J. Anderson (2017). "Allometric size: The scientific theory and extension to normal fat mass." European Journal of Pharmaceutical Sciences 109(Supplement): S59-S64.

Reeves, S., J. Bertrand, S. J. Obee, S. Hunter, R. Howard and R. J. Flanagan (2024). "A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status." British Journal of Clinical Pharmacology 90(1): 135-145.

Rhodin, M. M., B. J. Anderson, A. M. Peters, M. G. Coulthard, B. Wilkins, M. Cole, E. Chatelut, A. Grubb, G. J. Veal, M. J. Keir and N. H. Holford (2009). "Human renal function maturation: a quantitative description using weight and postmenstrual age." Pediatr Nephrol 24(1): 67-76.

Tralongo, F., C. Konecki, C. Feliu, A. Kaladjian and Z. Djerada (2023). "Association Between Clozapine Plasma Concentrations and Treatment Response: A Systematic Review, Meta-analysis and Individual Participant Data Meta-analysis." Clin Pharmacokinet 62(6): 807-818.