Leponex Mechanism of Action

Pharmacology: Pharmacodynamics: Clinically clozapine produces rapid and marked sedation, and exerts antipsychotic effects in patients with schizophrenia resistant to other antipsychotic agents. In such cases, clozapine has proven effective in relieving both positive and negative schizophrenic symptoms in short- and long-term trials.
Clozapine is unique in that it produces virtually no major extrapyramidal reactions such as acute dystonia and tardive dyskinesia. Furthermore, parkinsonian-like side effects and akathisia are rare. In contrast to classical antipsychotics, clozapine produces little or no prolactin elevation, thus avoiding adverse effects such as gynecomastia, amenorrhea, galactorrhea, and impotence.
Potentially serious adverse reactions caused by clozapine therapy are granulocytopenia and agranulocytosis occurring at an estimated incidence of 3% and 0.7% respectively (see Precautions).
Mechanism of action: Clozapine (Leponex) 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 behavior. It has only weak dopamine receptor-blocking activity at D₁, D₂, D₃ and D₅ receptors, but shows high potency for the D₄ receptor, in addition to potent anti-alpha-adrenergic, anticholinergic, antihistaminic, and arousal reaction-inhibiting effects. It has also been shown to possess antiserotoninergic properties.
Clinical Studies: Clinical studies in treatment-resistant schizophrenia (Clozapine study 16 & 30): The first study was Study 16, a randomized, double-blind, multicenter, parallel group comparative trial of clozapine versus chlorpromazine (CPZ) in hospitalized patients (aged 18 to 65 years and of either sex) with treatment resistant schizophrenia (DSM-II criteria). 151 such patients were randomly assigned to either clozapine (150-900 mg) or chlorpromazine (300-1800 mg) for 28 days with an optional extension up to 28 days (75 in clozapine group and 76 in chlorpromazine group). Efficacy was assessed by measuring mean change from baseline in the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) scores and the Nurses Observation Scale for Inpatient Evaluation (NOSIE-30). Throughout the study, and at endpoint, clozapine patients had a more rapid onset of action and showed significant improvement in BPRS items compared to chlorpromazine patients. At week 1, clozapine was statistically superior to CPZ in two items assessed: Motor retardation [0.67 vs. 0.12; p<0.05] and blunted affect [0.93 vs. 0.34; p<0.01]. At week 2, two more items also showed statistically significant improvements in clozapine group, emotional withdrawal [1.48 vs. 0.98; p<0.01] and unusual thought content [2.06 vs. 1.45; p<0.05]. At week 3, clozapine was statistically superior in 7 out of the 18 BPRS items assessed. At endpoint, clozapine showed statistically significant improvements in every item assessed. Results were similar for BPRS factors and CGI scores also. By week 2, statistically significant differences favoring clozapine were observed in the BPRS Total Score and maintained throughout the duration of study. Tests of comparative efficacy at endpoint showed clozapine to be significantly better for all five factors assessed: anxiety/depression (0.85 vs. 0.54; p<0.05), anergia (1.15 vs. 0.72; p<0.001), thought disturbance (1.80 vs. 1.28; p <0.01), activation (1.34 vs. 0.89; p<0.01), and hostile/suspiciousness (1.26 vs. 0.74; p<0.01)). At endpoint, clozapine showed statistically significant improvements in mean change in total BPRS score [22.53 vs. 14.64, p<0.001] and CGI [1.95 vs. 1.33, p<0.01]. Clozapine patients generally did better in the all NOSIE factors, except for social competence. Mean change from baseline showed statistically significant differences favoring clozapine in the improvement of irritability at weeks 3 (6.28 vs. 0.67, p<0.01) and week 4 (6.84 vs. 1.36, p<0.05). For most of the factors, particularly, total patient assets, there was clear evidence of an early onset of therapeutic benefit with clozapine, thus corroborating BPRS data, although no statistical difference was observed. At endpoint, clozapine was superior to CPZ for the following NOSIE factors: social interest (4.14 vs. 3.24), personal neatness (3.19 vs. 2.26), irritability (3.04 vs. 0.60) and manifest psychosis (6.32 vs. 4.24) as well as total assets (20.54 vs. 16.66).
Second study was Study 30, a randomized, double-blind, multicenter, parallel group, 6-week, comparative study of clozapine versus chlorpromazine plus benztropine. The study population included 319 treatment-resistant schizophrenic patients, between the ages of 18-60 years, who met DSM-III criteria for schizophrenia, refractory to treatment. Eligible patients were randomly assigned to either clozapine (up to 900 mg/day) or chlorpromazine plus benztropine (up to 1800 mg/day of chlorpromazine, plus 6 mg/day of benztropine). Efficacy was assessed using the BPRS score, CGI scale, and NOSIE-30. At the end of 6 weeks, clozapine was significantly superior to chlorpromazine in all "Positive", "Negative" and general symptoms of BPRS (p<0.001) except 'Grandiosity' and 'BPRS total score'. Clozapine showed a significantly superior change in CGI scale compared to chlorpromazine starting at week 1 (p<0.001). Clozapine was superior to chlorpromazine on all six NOSIE-30 factors and total assets starting at either week 1 or 2 (p < 0.05 to 0.001). Clozapine was statistically significant in the following NOSIE factors, social competence, social interest and personal neatness, and total assets (p<0.001), as well as irritability and motor retardation (p<0.01 <0.05, respectively).
Clinical study in risk of recurrent suicidal behavior (InterSePT Trial): The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT), a prospective, randomized, open label, international, parallel-group comparison of clozapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder (DSM-IV) judged to be at risk for re-experiencing suicidal behavior, lasting for 24 months. A total of 956 patients were randomized to either clozapine (starting with 25 mg/day, titrated upwards to 200-900 mg/day) or olanzapine (5-20 mg/day). The primary efficacy measure was time to a significant suicide attempt, including a completed suicide; hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized); or worsening of suicidality severity as demonstrated by "much worsening" or "very much worsening" from baseline in the CGI-SS-BP scale. Clozapine showed a statistically significant overall treatment effect compared to olanzapine for the primary efficacy measure (p=0.0309). Treatment effect for Type 1 events (a significant suicide attempt or hospitalization due to imminent suicide risk (including increased level of surveillance) was statistically significant in favor of clozapine (p=0.0316), with a hazard ratio [risk ratio] of 0.76 (95% C.I.: 0.58, 0.98). Similarly, the treatment effect for Type 2 events (worsening of suicidality severity as demonstrated by 7-point CGI-SS-BP change scale score of 6 or 7, or by implicit worsening of suicidality severity as demonstrated by occurrence of a Type 1 event) was statistically significant in favor of clozapine (p=0.0388), with a hazard ratio of 0.78 (95% C.I.: 0.61, 0.99). Probability (Standard Error, SE) of experiencing a Type 1 and Type 2 events was higher for olanzapine patients compared to clozapine patients at all visits. At week 104, the clozapine treatment group demonstrated a significantly lower probability of both Type 1 (24% vs. 32%; 95% C.I. 2%, 14%) and Type 2 event (28% vs. 37%; 95% C.I.: 2%, 15%).
Clinical study in psychosis in Parkinson's disease: A randomized, double-blind parallel group, multicenter trial was conducted to compare the efficacy of clozapine vs. placebo for the treatment of psychosis in Parkinson's disease (drug-induced psychosis unresponsive to usual management) and to compare the effect of clozapine vs. placebo on the motor function of patients with Parkinson's disease. Study participants included 60 male or female patients (32 clozapine, 28 placebo), who met the diagnosis criteria of idiopathic Parkinson's disease and with the following criteria of antiparkinsonian induced psychosis: psychotic symptoms for ≥2 weeks and requiring treatment (≥4 at item P1 or P3 of the PANSS; MMS > 20; no improvement of psychotic symptoms or unacceptable deterioration of motor function within a week despite usual therapeutic management; CGI-S >4. Patients received either clozapine or placebo for 4 weeks, starting with 10 days titration phase, up to the maximum dose of 50 mg (Period 2). All patients who completed period 2, received clozapine during 12 weeks with flexible dosage up to 150 mg/day (Period 3). Attempt of clozapine withdrawal (over 1 week) was made, with assessment visit 3 weeks later (Period 4). The mean change in CGI-S score (primary efficacy variable) was significantly greater in the clozapine group compared to the placebo group (-1.8 vs. -0.6; p=0.001) at the end of period 2. Significant improvement in CGI-S score was achieved at week 1 and maintained at all time points of period 2 for the clozapine group. At the end of Period 2, the mean change in the PANSS positive subscore (secondary efficacy variable) was significantly greater in the clozapine group than in the placebo group. Significant improvement in the PANSS positive subscores was obtained at week 1 and maintained at all subsequent time points. Reduction in scores of individual items were significant for all items. Clozapine treated patients continued to improve on both parameters during period 3. Improvement was slightly increased at end of period 3 for both the efficacy parameters, CGI-S (clozapine -2.5 vs. -1.8 for placebo) and PANSS (clozapine -7.7 vs. -4.8 for placebo).
Pharmacokinetics: 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 metabolized before excretion by CYP1A2 and 3A4, and to some extent by CYP2C19 and 2D6. Of the main metabolites only the desmethyl 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 feces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the feces.
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.
Toxicology: Non-Clinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see Use in Pregnancy & Lactation).
Mutagenicity: Clozapine and/or its metabolites were devoid of genotoxic potential when investigated for induction of gene mutations, chromosome aberrations and primary DNA-damage in a spectrum of in vitro mutagenicity tests. Likewise, no genotoxic activity was observed in vivo (bone marrow micronucleus test in mice).
Carcinogenicity: In Sprague-Dawley (CD) rats treated in the diet for 2 years, maximum tolerated doses of 35 mg/kg per day revealed no carcinogenic potential of clozapine. Likewise, no evidence of tumorigenic effects was obtained in two 1.5-year feeding studies in Charles River (CD) mice. In the first study, oral dose levels of up to 64 mg/kg per day were administered to males, and of up to 75 mg/kg per day to females respectively. In the second study, the highest dose for both sexes was 61 mg/kg per day.
Reproductive toxicity: No embryotoxic or teratogenic potential of clozapine was observed in rats or rabbits at daily oral doses of up to 40 mg/kg. In male rats receiving the same dosages for 70 days prior to mating, fertility was unaffected.
In female rats, fertility as well as pre- and postnatal development of the offspring was not adversely affected by oral clozapine treatment prior to mating (up to 40 mg/kg per day). When rats were treated at the same dosages during the later part of pregnancy and during lactation, survival rates of the young from lactating dams were lowered and the young were hyperactive. However, there was no lasting effect on pup development after weaning.