Destiq Mechanism of Action

Pharmacology: Pharmacodynamics: Mode of Action: It has been shown that desvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The clinical efficacy of desvenlafaxine is thought to be related to the potentiation of these neurotransmitters in the central nervous system.
Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors has been hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. In the same comprehensive binding profile assay, desvenlafaxine also lacked significant affinity for various ion channels, including calcium, chloride, potassium and sodium ion channels and also lacked monoamine oxidase (MAO) inhibitory activity. Desvenlafaxine lacked significant activity in the in vitro cardiac potassium channel (hERG) assay.
It is demonstrated that desvenlafaxine activity is predictive of antidepressant, anxiolytic and thermoregulatory actions, and pain inhibitory properties.
Pharmacokinetics: The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional in a dose range of 50 to 600 mg/day. The mean terminal half-life (t_½), is approximately 11 hours. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4 to 5 days. At steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.
Absorption and distribution: Desvenlafaxine succinate is well absorbed, with an absolute oral bioavailability of 80%. Mean time to peak plasma concentrations (T_max) is about 7.5 hours after oral administration. AUC and C_max of 6,747 ng·hr/mL and 376 ng/mL, respectively, are observed after multiple doses of 100 mg. Under fasting and fed conditions (high-fat meal) indicated that the C_max was increased about 16% in the fed state, while the AUCs were similar. This difference is not clinically significant; therefore, desvenlafaxine can be taken without regard to meals. The plasma protein binding of desvenlafaxine is low (30%) and is independent of drug concentration. Desvenlafaxine volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.
Metabolism and elimination: Approximately 45% of desvenlafaxine is excreted unchanged in urine. Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms, including UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17) and to a minor extent through oxidative metabolism. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine. CYP3A4 is the predominant cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine.
Geriatric: Administration of doses up to 300 mg, saw an age-dependent decrease in desvenlafaxine clearance, resulting in a 32% increase in C_max and a 55% increase in AUC values for those greater than 75 years of age, as compared with those from 18 to 45 years of age. No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose.
Hepatic insufficiency: The recommended dose in hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not recommended.
Renal insufficiency: The recommended dose in moderate renal impairment is 50 mg per day. Dosage adjustment (50 mg every other day) is recommended in severe renal impairment or ESRD. Doses should not be escalated in moderate or severe renal impairment, or ESRD.