Evaluation of clozapine forgiveness under imperfect adherence scenarios: a population pharmacokinetic simulation study.

Clozapine, the only drug approved by the FDA for treatment-resistant schizophrenia, operates within a narrow therapeutic range (0.35-0.60 mg/mL) and requires titration from 12.5 to 300-450 mg daily in two divided doses. Non-adherence, driven by adverse effects and logistic barriers, often manifests as missed or delayed doses. Clozapine's forgiveness, i.e., its capacity to sustain efficacy despite dosing errors, is poorly quantified. This study simulated the pharmacokinetics (PK) of clozapine to assess forgiveness across dosing scenarios. A one-compartment PK model (CL = 8.3 L/h, V = 2.8 L/kg, Ka = 0.69 h⁻, F = 0.27) with variability (22% CL, 14% V) was developed, and steady-state metrics for 200 mg twice-daily dosing were validated against literature reference. Simulations (200 mg, q12h) over 150 h for 500 subjects tested perfect adherence, 1-8 consecutively missed doses, and 1-10-h delays at steady state. Forgiveness was measured as AUC and time above minimum effective concentration (0.35 mg/L), expressed as percentages retained relative to perfect adherence. The perfect adherence yielded 0.44-0.62 mg/L, matching reference values. One missed dose reduced troughs to ~ 0.3 mg/L; eight consecutively missed doses dropped levels to near zero, slashing AUC and time above MEC to ~ 0%. A 10-h delay cuts AUC to 29% and time above MEC to 57%, with recovery by 150 h. Clozapine shows low forgiveness for missed doses, necessitating strict adherence but moderate delay tolerance, supporting flexible timings. Re-titration post-48 h is critical, guiding clinical management.