CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D) and the serotonin type 2A (5-HT) receptors. CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.
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Pharmacodynamics
Clozapine demonstrated binding affinity to the following receptors: histamine H (K 1.1 nM), adrenergic α (K 1.6 nM), serotonin 5-HT (K 4 nM), serotonin 5-HT (K 5.4 nM), muscarinic M (K 6.2 nM), serotonin 5-HT (K 6.3 nM), serotonin 5-HT (K 9.4 nM), dopamine D (K 24 nM), adrenergic α (K 90 nM), serotonin 5-HT (K 95 nM), serotonin 5-HT (K 120 nM), dopamine D (K 160 nM), dopamine D (K 270 nM), dopamine D (K 454 nM), and dopamine D (K 555 nM).
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Clozapine causes little or no prolactin elevation.
Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. 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.
Pharmacokinetics
Absorption
In man, CLOZARIL tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of CLOZARIL 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus, CLOZARIL may be administered with or without food.
Distribution
Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important.
[see Drug Interactions]
Metabolism and Excretion
Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100mg twice daily dosing.
N-
A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to area under the curve (AUC), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily.
Drug-Drug Interaction Studies
Fluvoxamine
A pharmacokinetic study was conducted in 16 schizophrenic patients who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated about 3-fold compared to baseline steady-state concentrations.
Paroxetine, Fluoxetine, and Sertraline
In a study of schizophrenic patients (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than 2-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline.
Specific Population Studies
Renal or Hepatic Impairment
No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses.
CYP2D6 Poor Metabolizers
A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m body surface area basis.
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Mutagenesis
Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the mammalian V79 in Chinese hamster cells, the unscheduled DNA synthesis in rat hepatocytes or the micronucleus assay in mice.
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Impairment of Fertility
Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m body surface area basis.
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