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Pharmacological particulars
Pharmacotherapeutic Group: Psychoanaleptics, antidepressants
ATCvet code: QN06AX11
Pharmacodynamic properties
Mirtazapine is an α2-adrenergic receptor antagonist noradrenergic and serotonergic antidepressant drug. The exact mechanism by which mirtazapine induces weight gain appears to be multifactorial. Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors in the central nervous system (CNS), and a potent inhibitor of histamine H1 receptors. Inhibition of 5-HT2 and histamine H1 receptors may account for the orexigenic effects of the molecule. Mirtazapine-induced weight gain may be secondary to changes in leptin and the tumour necrosis factor (TNF).
The product has an expected positive effect on feed intake by stimulating the appetite but this effect was not measured in the pivotal field trial. The only effect tested under field practice was on body weight: client- owned cats presented with a weight loss ≥ 5%, deemed clinically significant by the investigator, gained a statistically significant (p<0.0001) amount of weight, after 14 days of product administration (3.39% weight gain or average of 130 grams) compared to those cats administered placebo (0.09% weight gain or average of 10 grams).
Pharmacokinetic particulars
In a crossover study conducted with the product at 0.5 mg/kg in eight cats to determine the relative bioavailability of oral and transdermal 2% mirtazapine, the mean terminal half-life (25.6±5.5 hours) with topical administration was over 2X longer than the mean terminal half-life (8.63±3.9 hours) with oral administration. Bioavailability following topical administration was 34% (6.5-89%) compared to oral administration during the first 24 hours and 65% (40.1-128.0%) based on AUC0-∞. After a single topical administration, the mean peak plasma concentration of 21.5 ng/ml (±43.5) is reached in Tmax mean of 15.9 hours (1-48 hours). The mean AUC0-24 was 100 ng*h/ml (±51.7).
After administration of the product to 8 cats at a dose of 0.5 mg/kg once daily for 14 days, mean peak plasma concentration of 39.6 ng/ml (±9.72) is reached in Tmax mean of 2.13 hours (1-4 hours). The mean terminal half-life of mirtazapine was 19.9 h (±3.70) and the mean AUC0-24 was 400 ng*h/ml (±100).
In the target animal safety study, where cats received a higher dose (2.8-5.4 mg) than the label dose (2 mg) once daily for 42 days, steady state was achieved within 14 days. The median accumulation between first and 35th dose was 3.71X (based on AUC ratio) and 3.90X (based on Cmax ratio).