Cigarette smoking enhances plasma clozapine clearance and thus affects the clozapine dose requirement.

We compared clozapine daily dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in samples submitted for clozapine therapeutic drug monitoring (1996–2017).

There were 105,316/60,792 and 34,290/31,309 samples with dose information from male and female smokers/nonsmokers, respectively. There was information on the number of cigarettes smoked daily for 12,842 samples (8409 patients) and 3948 samples (2753 patients) from men and women, respectively. Of these, 574 and 253 samples were from men and women, respectively, who reported smoking 1–9 cigarettes daily.

In both sexes, the median clozapine doses in the nonsmokers were 75%–80% of those in the smokers, but the median plasma clozapine and norclozapine concentrations were 136% higher. The effect of smoking on the dose and on median plasma clozapine and norclozapine concentrations seemed maximal after 2–3, perhaps fewer, cigarettes daily in males. In females, the effect of smoking seemed to be near maximal after some 4–5 cigarettes per day.

The optimum target range for predose plasma clozapine may be different in smokers (0.35–0.45 mg L−1) as opposed to nonsmokers (0.50–0.60 mg L−1). That changes in clozapine clearance are likely near maximal with cigarette smoking as low as 2–3 d−1 in males, perhaps slightly more in females, emphasizes that covert or passive smoking may be an important factor in seemingly random changes in plasma clozapine concentration at constant dose.