Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: Selective serotonin reuptake inhibitors (SSRI), ATC code: N06 AB06

Mechanism of action
Sertraline is a potent and specific inhibitor of neuronal serotonin (5 HT) uptake in vitro, which results in the potentiation of the effects of 5-HT in animals. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets. It is devoid of stimulant, sedative or anticholinergic activity or cardiotoxicity in animals. In controlled studies in normal volunteers, sertraline did not cause sedation and did not interfere with psychomotor performance. In accord with its selective inhibition of 5-HT uptake, sertraline does not enhance catecholaminergic activity. Sertraline has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA or benzodiazepine receptors. The chronic administration of sertraline in animals was associated with down-regulation of brain norepinephrine receptors as observed with other clinically effective antidepressants and antiobsessional drugs.

Sertraline has not demonstrated potential for abuse. In a placebo-controlled, double-blind randomized study of the comparative abuse liability of sertraline, alprazolam and d- amphetamine in humans, sertraline did not produce positive subjective effects indicative of abuse potential. In contrast, subjects rated both alprazolam and d-amphetamine significantly greater than placebo on measures of drug liking, euphoria and abuse potential. Sertraline did not produce either the stimulation and anxiety associated with d-amphetamine or the sedation and psychomotor impairment associated with alprazolam. Sertraline does not function as a positive reinforcer in rhesus monkeys trained to self administer cocaine, nor does it substitute as a discriminative stimulus for either d-amphetamine or pentobarbital in rhesus monkeys.

Clinical efficacy and safety

Major Depressive Disorder
A study was conducted which involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline 50-200 mg/day. These patients (n=295) were randomized to continuation for 44 weeks on double-blind sertraline 50-200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline compared to those on placebo. The mean dose for completers was 70 mg/day. The % of responders (defined as those patients that did not relapse) for sertraline and placebo arms were 83.4% and 60.8%, respectively.


Cardiac Electrophysiology
In a dedicated thorough QTc study, conducted at steady state at supratherapeutic exposures in healthy volunteers (treated with 400 mg/day, twice the maximum recommended daily dose), the upper bound of the 2-sided 90% CI for the time matched Least Square mean difference of QTcF between sertraline and placebo (11.666 msec) was greater than the predefined threshold of 10 msec at the 4-hour postdose time point. Exposure-response analysis indicated a slightly positive relationship between QTcF and sertraline plasma concentrations [0.036 msec/(ng/mL); p<0.0001]. Based on the exposure response model, the threshold for clinically significant prolongation of the QTcF (i.e. for predicted 90% CI to exceed 10 msec) is at least 2.6-fold 
greater than the average Cmax (86 ng/mL) following the highest recommended dose of sertraline (200 mg/day) (see sections 4.4, 4.5, 4.8 and 4.9).

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Absorption
In man, following an oral once-daily dosage of 50 to 200 mg for 14 days, peak plasma concentrations of sertraline occur at 4.5 to 8.4 hours after the daily administration of the drug.
Food does not significantly change the bioavailability of sertraline tablets.

Distribution
Approximately 98% of the circulating drug is bound to plasma proteins.

Biotransformation
Sertraline undergoes extensive first-pass hepatic metabolism.
Based on clinical and in-vitro data, it can be concluded that sertraline is metabolized by multiple pathways including CYP3A4, CYP2C19 (see section 4.5) and CYP2B6. Sertraline and its major metabolite desmethylsertraline are also substrate of P-glycoprotein in-vitro.

Elimination
The mean half-life of sertraline is approximately 26 hours (range 22-36 hours). Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady state concentrations, which are achieved after one week of once-daily dosing. The half-life of N-desmethylsertraline is in the range of 62 to 104 hours. Sertraline and N-desmethylsertraline are both extensively metabolized in man and the resultant metabolites excreted in faeces and urine in equal amounts. Only a small amount (<0.2%) of unchanged sertraline is excreted in the urine.

Linearity/non-linearity
Sertraline exhibits dose proportional pharmacokinetics in the range of 50 to 200 mg.

Pharmacokinetics in specific patient groups

Adolescents and elderly
The pharmacokinetic profile in adolescents or elderly is not significantly different from that in adults between 18 and 65 years.

Hepatic impairment
In patients with liver damage, the half life of sertraline is prolonged and AUC is increased three fold (see sections 4.2 and 4.4).

Renal impairment
In patients with moderate-severe renal impairment, there was no significant accumulation of sertraline.

Pharmacogenomics

Plasma levels of sertraline were about 50% higher in poor metabolizers of CYP2C19 versus extensive metabolizers. The clinical meaning is not clear, and patients need to be titrated based on clinical response.