Clozapine

Additional information

Pharmacokinetics and dosing

Clozapine is extensively metabolized in the liver, predominantly by the cytochrome P450 enzymes CYP1A2 and CYP3A4, with smaller contributions from CYP2C19 and CYP2D6 among other enzymes [1-3]. Women in clinical trials have generally displayed higher dose-adjusted plasma concentrations of clozapine and its active metabolite norclozapine than men [4-6]. The magnitude of reported sex differences has ranged between approximately 15-60% for clozapine and norclozapine depending on population and methodology [7]. It is frequently suggested that this sex difference is derived primarily from a lower CYP1A2 activity in women, conferring a decreased clearance of clozapine [4-6]. However, several other factors may contribute, such as e.g. lower glomerular filtration rates, tubular secretion and hepatic blood flow in women on average, as well as sex differences in concomitant medications (e.g. oral contraceptives) and smoking which may influence the exposure of CYP1A2 metabolized drugs [5]. Clinical trials with relevant sex analyses of clozapine plasma concentrations have generally relied predominantly on trough or random samples [4]. This might theoretically exaggerate perceived sex differences in the total exposure of clozapine over the dosing interval; smaller fluctuations of clozapine concentrations during the dosing interval has been suggested in women compared to men, due to higher relative volumes of distribution for clozapine [7, 8]. Hence, sex differences in trough concentrations might be more pronounced than sex differences in e.g. mean plasma concentrations during the dosing interval [7, 8].No sex related dose adjustments are recommended by the manufacturer and no information regarding pharmacokinetic sex differences is provided in the summary of product characteristics [1].Therapeutic drug monitoring should be considered when prescribing clozapine, especially in the event of anticipated pharmacokinetic interactions, suspected toxicity or inadequate therapeutic effects in relation to administered doses.

Effects

No prospective, controlled trials examining sex differences in clozapine therapeutic efficacy have been identified. Observational data are conflicting, with some studies indicating a favorable treatment response rate in women compared to men [11-13], whereas others have indicated the opposite [14-16] or failed to demonstrate significant sex effects [17]. Differences in patient populations, baseline conditions and evaluated endpoints between the different studies makes it difficult to perform meaningful comparisons. The authors of a systematic review published in 2019 concluded that although female sex is frequently associated with a more beneficial response to antipsychotics in schizophrenia, it is not yet clear whether this holds true for clozapine [18].

Adverse effects

Several observational studies have indicated that women might be disproportionally affected by clozapine-induced neutropenia including agranulocytosis [19-22] and immunological sex differences have been proposed as a plausible explanation [23]. According to the authors of a systematic review, available evidence suggests that metabolic adverse effects such as hypertension and dyslipidemia might be more common in men taking clozapine, whereas women may be more prone to gain weight and develop diabetes respectively [18]. However, conflicting results have been reported [24-27]. Although female sex is generally considered an independent risk factor for drug induced QT-interval prolongation and development of Torsades de Pointes [28], reported sex differences for clozapine appear inconclusive in this respect [18].

Reproductive health issues

Use of combined hormonal contraceptives containing ethinylestradiol has been associated with an increased exposure to clozapine [9, 10]. Regarding other drug interaction aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner). Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).