Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: antidepressants, selective serotonin reuptake inhibitors ATC-code: N 06 AB 10

Mechanism of action
Escitalopram is a selective inhibitor of serotonin (5-HT) re-uptake with high affinity for the primary binding site. It also binds to an allosteric site on the serotonin transporter, with a 1000 fold lower affinity.


Escitalopram has no or low affinity for a number of receptors including 5 HT1A, 5 HT2, DA D1 and D2 receptors, α1, α2-, β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors.
The inhibition of 5 HT re-uptake is the only likely mechanism of action explaining the pharmacological and clinical effects of escitalopram.

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Pharmacodynamic effects
In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 4.3 ms (90% CI: 2.2, 6.4) at the 10 mg/day dose and 10.7 ms (90% CI: 8.6, 12.8) at the supratherapeutic dose 30 mg/day (see section 4.3, 4.4, 4.5, 4.8 and 4.9).

Clinical efficacy

Major depressive episodes
Escitalopram has been found to be effective in the acute treatment of major depressive episodes in three out of four double-blind, placebo controlled short-term (8-weeks) studies.

In a long-term relapse prevention study, 274 patients who had responded during an initial 8-week open label treatment phase with escitalopram 10 or 20 mg/day, were randomised to continuation with escitalopram at the same dose, or to placebo, for up to 36 weeks. In this study, patients receiving continued escitalopram experienced a significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.


Social anxiety disorder
Escitalopram was effective in both three short-term (12-week) studies and in responders in a 6 months relapse prevention study in social anxiety disorder. In a 24-week dose-finding study, efficacy of 5, 10 and 20 mg escitalopram has been demonstrated.

Generalised anxiety disorder
Escitalopram in doses of 10 and 20 mg/day was effective in four out of four placebo-controlled studies.

In pooled data from three studies with similar design comprising 421 escitalopram-treated patients and 419 placebo-treated patients, there were 47.5% and 28.9% responders respectively and 37.1% and 20.8% remitters. Sustained effect was seen from week 1.

Maintenance of efficacy of escitalopram 20 mg/day was demonstrated in a 24- to 76-week randomised, maintenance of efficacy study in 373 patients who had responded during the initial 12-week open label treatment.

Obsessive-compulsive disorder
In a randomised, double-blind, clinical study,, 20 mg/day escitalopram separated from placebo on the Y-BOCS total score after 12 weeks. After 24 weeks, both 10 and 20 mg/day escitalopram were superior as compared to placebo.

Prevention of relapse was demonstrated for 10 and 20 mg/day escitalopram in patients who responded to escitalopram in a 16 week open-label period and who entered a 24 week, randomised, double blind, placebo controlled period.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption
Absorption is almost complete and independent of food intake. Mean time to maximum concentration (mean Tmax) is 4 hours after multiple dosing. As with racemic citalopram, the absolute bio-availability of escitalopram is expected to be about 80%.

Distribution
The apparent volume of distribution (Vd,β/F) after oral administration is about 12 to 26 L/kg. The plasma protein binding is below 80% for escitalopram and its main metabolites.


Biotransformation
Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides. After multiple dosing the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5%, respectively, of the escitalopram concentration. Biotransformation of escitalopram to the demethylated metabolite is mediated primarily by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible.

Elimination
The elimination half-life (t½ β) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) is about 0.6 L/min. The major metabolites have a significantly longer half-life. Escitalopram and major metabolites are assumed to be eliminated by both the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in the urine.

Linearity
There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 1 week. Average steady- state concentrations of 50 nmol/L (range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.

Elderly patients (> 65 years)
Escitalopram appears to be eliminated more slowly in elderly patients compared to younger patients. Systemic exposure (AUC) is about 50 % higher in elderly compared to young healthy volunteers (see section 4.2).

Reduced hepatic function
In patients with mild or moderate hepatic impairment (Child-Pugh Criteria A and B), the half-life of escitalopram was about twice as long and the exposure was about 60% higher than in subjects with normal liver function (see section 4.2).

Reduced renal function
With racemic citalopram, a longer half-life and a minor increase in exposure have been observed in patients with reduced kidney function (CLcr 10-53 ml/min). Plasma concentrations of the metabolites have not been studied, but they may be elevated (see section 4.2).

Polymorphism
It has been observed that poor metabolisers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolisers. No significant change in exposure was observed in poor metabolisers with respect to CYP2D6 (see section 4.2).