Therapeutic Clozapine Monitoring Using Dose-Related Reference Range

Abstract

BACKGROUND: Advancements in the therapeutic drug monitoring (TDM) have increased the accuracy and safety of clozapine dosing, particularly for patients with treatment-resistant schizophrenia. The relevance and applicability of 2 monitoring frameworks were assessed, the therapeutic and dose-related reference ranges (TRR and DRR, respectively), by comparing the differences in the measured clozapine trough plasma concentration (C0). METHODS: All steady-state clozapine C0 values measured between 2011 and 2021 were retrospectively analyzed. The TRR was defined as 350-600 ng/mL according to the consensus guidelines of the Arbeitsgemeinschaft für Neuropsychopharmakology und Pharmakopsychiatrie. The DRR was calculated using the dose-related concentration (DRC), as defined in the 2017 AGNP consensus update. RESULTS: A total of 755 clozapine C0 measurements from 427 Tunisian patients were analyzed. The mean patient age was 36.5 ± 9.5 years, with a male-to-female ratio of 4.1. The mean daily clozapine dose was 472.5 ± 273.7 mg. A total of 31.9% of C0 values fell within the TRR, whereas 48.7% and 19.3% fell within the sub- and supratherapeutic ranges, respectively. In contrast, 66.8% of the values were within the DRR, with 16.3% and 16.9% within the sub- and supratherapeutic ranges, respectively. A strong positive correlation was observed between C0 and the administered dose (r = 0.81, P < 0.001). CONCLUSIONS: These plasma clozapine levels aligned more with the DRR than with the TRR, particularly when individual dosing was considered. The DRR may offer higher precision in guiding therapeutic decisions and dose adjustments. Further prospective studies are warranted to optimize the use of the DRR in clinical practice and validate the value of the DRR in predicting clozapine efficacy and safety.