Clinical Pharmacology
Apo-Clozapine (clozapine), a dibenzodiazepine derivative, is an atypical antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by conventional antipsychotics. In contrast to conventional antipsychotics, clozapine produces little or no prolactin elevation. Clozapine exerts potent anticholinergic, adrenolytic, antihistaminic and antiserotoninergic activity.

Controlled clinical trials indicate that clozapine improves both positive and negative symptoms.

Patients on rare occasions may report an intensification of dream activity during clozapine therapy. Rapid eye movement (REM) sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep. 

As is true of more typical antipsychotic drugs, clinical EEG studies have shown that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop.


Pharmacokinetics
The absorption of orally administered clozapine is 90 to 95%. Food does not affect either the rate or the extent of absorption. Clozapine is subject to first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.

Plasma concentrations show large inter-individual differences, with peak concentrations occurring approximately 2.5 hours (range: 1 to 6 hours) after dosing. In a dose range of 37.5 mg b.i.d. to 150 mg b.i.d., the area under the curve (AUC) and the peak plasma concentration (Cmax) increase linearly in a dose-related fashion.

Clozapine is approximately 95% bound to plasma proteins. The elimination of clozapine is biphasic with a mean terminal half-life of 12 hours (range: 6 to 30 hours, calculated from 3 steady-state in vivo studies). 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. Clozapine is almost completely metabolized prior to excretion. Only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted as metabolies in the urine and 30% in the feces.

Recent studies suggest that there is a significant correlation between clozapine plasma levels and clinical response. The concentrations of clozapine, and its major metabolite norclozapine, were significantly higher in responders than in non responders although the mean doses of clozapine did not differ between the 2 groups. Of the main metabolites, only norclozapine was found to be active. In patients who responded to treatment, plasma clozapine levels reached at least 350 to 370 ng/mL.

Bioavailability
A study was performed to compare the bioavailabity of Apo-Clozapine 100 mg tablets (Apotex Inc.) with respect to a reference product Clozaril (Novartis Canada Inc., Canada) by comparing the rate and extent of absorption of clozapine.

Summary Table of the Comparative Bioavailability Date For Steady State Studies Apo-Clozapine

• From measured and log transformed data 
• uncorrected for potency 
• Geometric Mean - Dose Normalized to 400 mg clozapine given as equal 12-hourly doses 
• Arithmetic Mean (CV %)