Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

ATC code: N05AH02
Mechanism of action/Pharmacodynamics
Leponex, a tricyclic dibenzodiazepine derivative, is an antipsychotic agent that differs from conventional antipsychotic agents in terms of both its pharmacology and its clinical effect.
In pharmacological experiments, clozapine 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 as well as potent anti-alpha-adrenergic, anticholinergic, antihistaminic and arousal-reaction- inhibiting effects. It also possesses antiserotoninergic properties.

Clinical efficacy
Clinically, Leponex produces rapid and marked sedation and exerts a potent antipsychotic effect, particularly in patients resistant to other drug treatment. In such cases, it brings about an improvement in both positive (productive) and negative symptoms of schizophrenia. A clinically significant improvement was observed in about one-third of patients within the first six weeks of treatment and in approx. 60% of patients in whom treatment was continued for up to 12 months. In addition, improvement has been described in some forms of perceptual dysfunction.
In a two-year study directly comparing Leponex with another atypical antipsychotic agent, it was shown that Leponex significantly reduced the risk of suicidal behaviour in patients with schizophrenia or schizoaffective disorder. There have been no studies on either of the acute effect of short-term treatment on suicidality or of the anti-suicidal effect in patients with other psychiatric disorders; use of Leponex in these indications is therefore not advisable. Leponex must not be used in patients who have depression with psychotic symptoms.
In the study, 980 patients were randomised to treatment either with Leponex or with the active control; 62% of the patients suffered from schizophrenia, 38% from schizoaffective disorder. For statistical reasons, two types of suicidal events were evaluated (type 1 and type 2 events). After 2 years the cumulative probability of a type 1 event (i.e. unambiguous suicide attempt, completed suicide or hospitalisation to prevent suicide) was lower in patients treated with Leponex (24%) than in patients treated with the other atypical antipsychotic agent (32%): 

0.5
Cumulative probability


Clozapin
Control substance
0.4

32%
0.3
24%
0.2

0.1
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time, months
Figure: Kaplan-Meier estimate of cumulative probability of an unambiguous suicide attempt, completed suicide or hospitalisation to prevent suicide (type 1 events).

The rate of occurrence of type 2 events (suicidality other than type 1 events, assessed by several scores) was 28% with clozapine and 37% with the other atypical antipsychotic agent.
Five successful suicides were reported in patients treated with clozapine and three in patients given the active control; this difference was not statistically significant.
Furthermore, epidemiological studies showed the rate of suicide and attempted suicide to be approximately seven times lower in Leponex-treated patients than in schizophrenic patients who did not receive Leponex.
Severe extrapyramidal reactions such as acute dystonia or full-blown parkinsonism are virtually unknown with Leponex, while Parkinson-like side effects and akathisia are rare. In contrast to conventional antipsychotic agents, Leponex causes little or no increase in prolactin levels, making adverse effects such as gynaecomastia, amenorrhoea, galactorrhoea and impotence less likely.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
The absorption of orally administered Leponex is 90 to 95%; neither the rate nor the extent of absorption is influenced by food. The active substance of Leponex, clozapine, is subject to moderate first-pass metabolism; the absolute bioavailability is 50 to 60%. Peak blood levels are reached on average after 2.1 hours (range 0.4 to 4.2 hours) under steady-state conditions involving twice-daily administration.
Dose 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 trough plasma levels.

Distribution
The volume of distribution is 1.6 litres/kg. Clozapine is almost 95% bound to plasma proteins.

Metabolism
Prior to elimination, clozapine is almost completely metabolised by CYP1A2 and 3A4 and to some extent by CYP2C19 and 2D6.
Of the main metabolites, only desmethylclozapine is pharmacologically active. Its effect is similar to that of clozapine but considerably weaker and of shorter duration.

Elimination
Elimination of clozapine is biphasic, with a mean terminal half-life of 12 hours (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 were detected in the urine and faeces. Approximately 50% of the dose administered is excreted as metabolites in the urine and 30% in the faeces.

Pharmacokinetics in special populations
Although no pharmacokinetic studies are available, the biotransformation and excretion data for Leponex indicate that particular caution is required in patients with hepatic, biliary or renal disease. Leponex is contraindicated in severe cases of such diseases due to the risk of accumulation.