Analysis of TDM data of clozapine: A daily consumption of less than 10 cigarettes is sufficient for maximum induction of clozapine metabolism

Introduction: Clozapine is particularly used in the treatment of schizophrenic patients who are refractory to other antipsychotics. Highly variable plasma concentrations are found in patients receiving the same dose of clozapine. Therefore, routine therapeutic drug monitoring (TDM) is recommended to increase the response rate and to minimize dose-dependent toxic adverse events. Clozapine is metabolized to a major extent by the cytochrome P450 enzyme CYP1A2. Cigarette smoke is a potent inducer of CYP1A2. The majority of schizophrenic patients are smokers. It was, therefore, the primary objective of this study to investigate the dose-dependent effect of smoking on the pharmacokinetics of clozapine. Materials and Methods: A retrospective study was conducted of data already collected from psychiatric patients in several Bavarian hospitals during routine TDM from 2000 to 2010. A total of 2493 clozapine serum concentrations assayed in our laboratory was anonymously stored in our TDM data bank in addition with information on date and time of blood withdrawal, clozapine dose, dosing schedule, duration of treatment, comedication, patient's sex, age, body weight and height, diagnosis, smoking behaviour, caffeine consumption, occurrence of adverse effects and clinical status. Clozapine concentrations were not only analyzed in relation to therapeutic reference range but also to a dose-related reference range which was calculated with a fixed total clearance value of 29.6 ± 14.1 l/h reported in the literature. Serum concentrations of patients with comedications which are known to interact with the metabolism of clozapine were excluded for most evaluations. Results: The total clearance of clozapine for non-smoking women was 23% lower than for men (17.9 ± 8.8 versus 23.3 ± 11.3 l/h). Smoking increased the total clearance of women by 63% (29.2 ± 19.1 l/h) and of men by 46% (34.0 ± 17.3 l/h). There were no significant differences in oral clearance of clozapine between patients smoking 1–10, 11–20 or more cigarettes daily. Serum concentrations of non-smoking women and men exceeded the upper limit of the therapeutic window twice to five-fold as often as smoker. In addition, in the non-smoking subgroup 48% of women and 36% of men displayed clozapine concentrations above the upper limit of the dose-related reference range (smokers: ♀ 7%, ♂ 23%). Conclusion: Serum concentrations of clozapine are mainly influenced by smoking status. Even a daily consumption of 1–10 cigarettes is sufficient for maximum induction of clozapine metabolism. To avoid adverse effects non-smokers should receive an about 50% lower starting dose of clozapine. In addition, similar clozapine dose reduction should be considered during smoking cessation.