Devert-50/Devert-100 Mechanism of Action

Antidepressant.
Pharmacology: Mechanism of Action: While the exact mechanism of the antidepressant action is unknown, the clinical efficacy of desvenlafaxine is related to an increased action of these neurotransmitters in the central nervous system through inhibition of their reuptake. Desvenlafaxine is a potent and selective inhibitor of the reuptake of serotonin and noradrenaline (SNRI).
Pharmacodynamics: Desvenlafaxine has no significant affinity for various receptors, including muscarinic-cholinergic receptors, H₁ histaminergic or α₁-adrenergic receptors in vitro. It also showed no inhibitory activity on monoamine oxidase (MAO).
Pharmacokinetics: The single-dose pharmacokinetics of desvenlafaxine is linearly proportional to the dose in a dose range from 50 to 600 mg/day. With administration once daily, plasma concentrations at steady state are achieved in approximately 4-5 days. At steady-state, the accumulation of multiple doses of desvenlafaxine is linear and predictable from a single-dose pharmacokinetic profile. The mean terminal half-life (t_1/2) is approximately 11 hours.
Absorption and Distribution: Desvenlafaxine succinate monohydrate is well absorbed with an absolute oral bioavailability of 80%. The mean time to peak plasma concentration (T_max) is about 7.5 hours after oral administration. The volume of distribution at steady state after intravenous administration is 3.4 L/kg, indicating distribution into non-vascular compartments. The plasma protein binding of desvenlafaxine is low (30%) and is independent of the drug concentration.
Effects of Food: A study of the effect of the presence of food involving the administration of desvenlafaxine in fasting healthy subjects and in the presence of food (meals with high fat content) indicated that the C_max increased approximately 16% in the presence of food, while the AUCs were similar. This difference is not clinically significant; therefore, desvenlafaxine may be taken without regard to meals.
Metabolism and Elimination: Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms, including UGT1A1, UGT1A3, UGT2B4, UGT2B15 and UGT2B17) and to a lesser degree, by means of oxidative metabolism. CYP3A4 is the predominant cytochrome P450 isozyme that acts as a mediator of the oxidative metabolism (N-demethylation) of desvenlafaxine. Approximately 45% of desvenlafaxine is excreted unchanged in the urine, 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-Didesmethylvenlafaxine) in the urine.
In Vitro Studies: Drugs Metabolized by CYP3A4: In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isoenzymes.
P-glycoprotein transporter: In vitro, desvenlafaxine is not a substrate or inhibitor of the P-glycoprotein transporter.
Inhibitors of other CYP enzymes: Based on in vitro data, it is not expected that drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19 and 2E1 have significant impact on the pharmacokinetic profile of desvenlafaxine.
Special Populations: Geriatric Use: In clinical studies of MDD treated with desvenlafaxine, no overall differences in safety or effectiveness were observed between these patients and younger patients; However, possible reduced renal clearance of desvenlafaxine should be considered when determining the dose.
Pediatric use: The safety and efficacy in patients under 18 years of age have not been established.
Renal Impairment: Elimination was significantly correlated with creatinine clearance. Dosage adjustment is necessary in patients with significant impairment of renal function. Supplemental doses should not be given to patients after dialysis.