Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antidepressants
ATC code: N06AX11
Mechanism of action/pharmacodynamic effects
Mirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, because 5-HT2- and the 5- HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2 receptors and the R (-) enantiomer by blocking 5-HT3 receptors.
Clinical efficacy and safety
The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has only limited effects (e.g. orthostatic hypotension) on the cardiovascular system.
The effect of mirtazapine on QTc interval was assessed in a randomized, placebo and moxifloxacin controlled clinical trial involving 54 healthy volunteers using a regular dose of 45 mg and a supra-therapeutic dose of 75 mg. Linear e-max modelling suggested that prolongation of QTc intervals remained below the threshold for clinically meaningful prolongation (see section 4.4).
Pediatric population
Two randomized, double-blind, placebo-controlled trials in children aged between 7 and 18 years with major depressive disorder (n=259) using a flexible dose for the first 4 weeks (15- 45mg mirtazapine) followed by a fixed dose (15, 30 or 45 mg mirtazapine) for another 4 weeks failed to demonstrate significant differences between mirtazapine and placebo on the primary and all secondary endpoints. Significant weight gain (≥7%) was observed in 48.8% of the mirtazapine treated subjects compared to 5.7% in the placebo arm. Urticaria (11.8% vs 6.8%) and hypertriglyceridaemia (2.9% vs 0%) were also commonly observed.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
After oral administration of mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after approx. two hours. Food intake has no influence on the pharmacokinetics of mirtazapine.

Distribution
Binding of mirtazapine to plasma proteins is approx. 85%.

Biotransformation
Major pathways of biotransformation are demethylation and oxidation followed by conjugation. In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas the CYP3A4 is considered to be responsible for the formation of the N- demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.

Elimination
Mirtazapine is extensively metabolized and eliminated via the urine and feces within a few days.฀
The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation.

Linearity/non-linearity
Mirtazapine displays linear pharmacokinetics within the recommended dose range.

The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.