The integrated Lei-CNS PBPK-PD model effectively predicts clozapine brain disposition and D2 receptor occupancy in humans.

AIM: Clozapine, used for treatment-resistant schizophrenia, has a narrow therapeutic window and highly variable plasma pharmacokinetics (PK), necessitating careful monitoring. Direct measurement of unbound brain PK in humans is unethical. To develop a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to predict clozapine brain extracellular fluid (brainECF) PK in rats and humans and D2 receptor occupancy (RO) in humans. METHODS: A previously developed rat CNS PBPK model (LeiCNS-PK3.5), containing brain metabolism, was extended to include active blood-brain barrier (BBB) influx transport and neutral lipid binding (LeiCNS-PK3.6). LeiCNS-PK3.6 was validated against observed brainECF clozapine concentrations in rats. For human translation, species-specific transporter and enzyme parameters were applied. A receptor binding kinetics model, with association and dissociation rate constants, was developed to predict D2 RO based on unbound brainECF clozapine concentrations and validated using PET-derived clinical data. RESULTS: The LeiCNS-PK3.6 model significantly improved the prediction accuracy of brainECF clozapine PK in rats compared with previous versions. In humans, predicted brainECF concentrations aligned with expected therapeutic ranges. The PBPK-PD model accurately predicted D2 RO in most patients, suggesting polymorphisms, smoking and dissociation rate constant (koff) may affect prediction accuracy. CONCLUSIONS: The integrated CNS PBPK-PD model effectively predicts clozapine brain disposition and D2 RO in humans. This framework offers a valuable tool to explore inter-individual variability (e.g., CYP1A2 polymorphisms, smoking and koff), supporting personalized dosing strategies and improved safety in clozapine therapy.