Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antidepressant, non-selective monoamine reuptake inhibitors ATC code: N06AA04

Mechanism of action
Clomipramine is a tricyclic antidepressant, which therapeutic activity is believed to be based on its ability to inhibit the neuronal reuptake of noradrenaline (NA) and serotonin (5-HT) released in the synaptic cleft, with inhibition of 5-HT reuptake being the more important of these activities. Clomipramine also has a wide pharmacological spectrum of action, which includes alpha1-adrenolytic, anticholinergic, antihistaminic, and anti-serotonergic (5-HT-receptor blocking) properties.
Pharmacodynamic effects
Anafranil acts on the depressive syndrome as a whole, including in particular typical features such as psychomotor retardation, depressed mood, and anxiety. The clinical response usually sets in after 2-3 weeks of treatment.
Clomipramine also exerts a specific effect on obsessive-compulsive disorder distinct from its antidepressant effects.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration, clomipramine is completely absorbed from the gastrointestinal tract.
The systemic bioavailability of unchanged clomipramine is reduced to about 50% by first-pass metabolism to the active metabolite, N-desmethylclomipramine.

Following single dose administration of Anafranil 25 mg coated tablet and Anafranil 75 mg sustained- release tablet, the mean maximum plasma concentration (Cmax) of clomipramine were 63.37 ± 12.71 ng/mL (Tmax 4.83 ± 0.39 hr) and 32.55 ± 8.10 ng/mL (Tmax 9.00 ± 1.81 hr), respectively. The recommended dose for treatment of depression, which is 75 mg daily, administered either as coated tablets of 25 mg t.i.d. or as a sustained-release tablet of 75 mg once daily, produces steady-state plasma concentrations ranging from about 20 to 175 ng/mL.

The steady-state concentrations of the active metabolite N-desmethylclomipramine follow a similar pattern.
However, at a dose of 75 mg Anafranil per day, the metabolite levels are 40-85% higher than those of clomipramine.

Distribution
Clomipramine is 97.6% bound to plasma proteins.
Clomipramine is extensively distributed throughout the body with the apparent distribution volume is about 12 to 17 L/kg bodyweight.
Concentrations in cerebrospinal fluid are about 2% of the plasma concentration.
Clomipramine passes into maternal milk in concentrations similar to those in plasma and crosses the placenta.

Metabolism
The primary route of clomipramine metabolism is demethylation to form the active metabolite, N- desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, primary CYP3A4, CYP2C19, and CYP1A2. Clomipramine and N- desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-N- desmethylclomipramine. Clomipramine is hydroxylated at the 2-position and N- desmethylclomipramine can be further demethylated to form didesmethylclomipramine. The 2- and 8- hydroxy metabolites are excreted primarily as glucuronides in the urine. Elimination of the active components, clomipramine and N-desmethylclomipramine, by formation of 2- and 8-hydroxy clomipramine is catalyzed by CYP2D6.

Elimination
Clomipramine is eliminated from the blood with a mean half-life of 21 h (range: 12-36 h), and desmethylclomipramine with a mean half-life of 36 h.

About two thirds of a single dose of clomipramine are excreted in the form of water-soluble conjugates in the urine and approximately one third in the feces. The quantity of unchanged clomipramine and desmethylclomipramine excreted in the urine is about 2% and 0.5% of the dose administered, respectively.
Food effect
Food has no significant impact on the pharmacokinetics of clomipramine. A slight delay in the onset of absorption may be observed with the administration of Anafranil with food.

Proportinality of dosage
The drug shows dosage-proportional pharmacokinetics in a dosage range of 25 to 150 mg.

Effect of age
In elderly patients, clomipramine has relatively low clearance in comparison to younger adult patients. It is reported to reach a therapeutic steady state at doses lower than that reported for middle-age patients.
Clomipramine should be used with caution in elderly patients.

Renal impairment
There are no specific reports describing the pharmacokinetic of the drug in patients with renal impairment.
Although the drug is excreted as inactive metabolites in the urine and feces, the accumulation of inactive metabolites may subsequently result in the accumulation of the parent drug and its active metabolite. In moderate and severe renal impairment, it is recommended to monitor the patient during the treatment.

Hepatic impairment
Clomipramine is extensively metabolised in the liver by CYP2D6, CYP3A4, CYP2C19 and CYP1A2, hepatic impairment may impact on its pharmacokinetics. In patients with liver impairment, clomipramine should be administered with caution.

Ethnic sensitivity
Although the impact of ethnic sensitivity and race on the pharmacokinetics of clomipramine has not been studied extensively, the metabolism of clomipramine and its active metabolite is governed by genetic factors leading to poor and extensive metabolism of the drug and its metabolite. The metabolism of clomipramine in Caucasians population may not be extrapolated to Asians, in particular Japanese and Chinese because of the pronounced differences of metabolism of clomipramine between these two ethnic groups.

Formulations with sustained release
The sustained release of clomipramine from a sustained-release tablet leads to a lower pharmacokinetic profile, because therapeutic plasma concentrations are maintained over 24 hours. The maximal mean plasma concentrations are attained after 9 hours after administration. After administration of Anafranil 75 mg sustained-release tablets, reported Cmax maintains half the values of Cmax after administration of Anafranil 25 mg coated tablets 3-times daily, however, the total expostion remains unchanged. Cmin and Cmax, which are maintained in steady-stade, lie within the therapeutic range after several administrations of Anafranil sustained-release. Anafranil coated tablets and sustained-release tablets are bioequivalent.

Clinical trials
There are currently no clinical trials performed with Anafranil.