Clozapine

Clozapine has been shown to be an antipsychotic agent that is different from classic antipsychotics.

In pharmacological experiments, the compound does not induce catalepsy or inhibit apomorphine- or amphetamine-induced stereotyped behaviour. It has only weak dopamine-receptor-blocking activity at D₁, D₂, D₃ and D₅ receptors, but shows high potency for the D₄ receptor.

Pharmacodynamic effects

Clozapine has potent anti-alpha-adrenergic, anticholinergic, antihistaminic, and arousal-reaction-inhibiting effects. It has also been shown to possess antiserotoninergic properties.

Compared to classic antipsychotics, clozapine produces fewer major extrapyramidal reactions such as acute dystonia, parkinsonian-like side effects and akathisia. In contrast to classic antipsychotics, clozapine produces little or no prolactin elevation, thus avoiding adverse effects such as gynaecomastia, amenorrhoea, galactorrhoea, and impotence.

A potentially serious adverse reaction caused by clozapine therapy is granulocytopenia and agranulocytosis occurring at an estimated incidence of 3% and 0.7%, respectively. In view of this risk, the use of clozapine should be limited to patients who are treatment-resistant or patients with psychosis in Parkinson’s disease when other treatment strategies have failed and in whom regular haematological examinations can be performed.

Absorption

The absorption of orally administered clozapine is 90 to 95%; neither the rate nor the extent of absorption is influenced by food.

Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.

Distribution

In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 l/kg. Clozapine is approximately 95% bound to plasma proteins.

Biotransformation/metabolism

Clozapine is almost completely metabolised before excretion by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Of the main metabolites only the demethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine but are considerably weaker and of short duration.

Elimination

Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). After single doses of 75 mg the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days.

Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.

Linearity/non-linearity

Dosage increases from 37.5 mg to 75 mg and 150 mg given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.