Effect of Fluvoxamine Comedication on the Formation of Clozapine Metabolites Associated With Clinical Effect or Toxicity in Smoking and Nonsmoking Patients.

BACKGROUND

Fluvoxamine (FLU) comedication increases clozapine (CLZ) exposure and lowers dose requirements by inhibiting its metabolism. Formation of N-desmethylclozapine (DCL), CLZ-N-oxide (NOX), and reactive nitrenium ions (CYS-conjugates) has been associated with cognitive function, cardiac damage, and granulocyte toxicity, respectively. This study explored how FLU affects the formation of these CLZ metabolites in smokers and non-smokers separately.

METHODS

The study used therapeutic drug monitoring (TDM) data from 302 patients (52% smokers) concurrently using FLU (n = 19) or CLZ without FLU (controls; n = 283) performed during January 2019 to October 2023. Serum CLZ and DCL levels were measured during routine TDM, while NOX and CYS-conjugates were obtained by reprocessing UHPLC-HRMS data. Concentration-to-dose ratio (CD; exposure) of CLZ and metabolic ratios (MR; formation) were compared using multivariate linear regression, stratified by smoking status and adjusted for age, sex, and sampling time.

RESULTS

Smoking patients comedicated with FLU showed a 3.2-fold higher CLZ CD ratio (P < 0.0001) and reduced formation of DCL (-38%, P < 0.0001), NOX (-49%, P < 0.0001), CLZ-8-CYS1+ (-43%, P = 0.0103), and NOX-CYS1+ (-62%, P = 0.003) compared with smokers receiving CLZ alone. In non-smokers, FLU treatment led to a higher CLZ CD ratio (2.6-fold, P = 0.0012) and reduced formation of DCL (-42%, P = 0.0007), NOX (-52%, P = 0.0009), and NOX-CYS1+ (-73%, P = 0.0073) compared with the non-smoking controls.

CONCLUSIONS

This study shows that FLU increases CLZ exposure regardless of smoking status and significantly reduces the formation of metabolites that have been linked to cognition, metabolic side effects, myocarditis, and granulocyte toxicity. Whether FLU alters these clinical outcomes by reducing the metabolic formation needs to be investigated further in controlled studies with access to data on treatment efficacy and side effects.