Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and...

Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization.

Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations.

The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance.

Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.