Pristiq Mechanism of Action

Pharmacology: Mechanism of Action: Non-clinical studies have shown that desvenlafaxine succinate is a selective SNRI. The efficacy of desvenlafaxine succinate is thought to be related to the potentiation of the neurotransmitters serotonin and norepinephrine in the central nervous system.
Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H₁-histaminergic, or α₁-adrenergic receptors in vitro. 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.
In preclinical rodent models, desvenlafaxine demonstrated activity predictive of antidepressant, anxiolytic and thermoregulatory actions, and pain inhibitory properties.
Major Depressive Disorder Studies: Pristiq was studied in a clinical programme involving 3292 patients meeting DSM-IV criteria for major depressive disorder. Overall, doses of 50-400 mg/day were shown to be effective in 4 out of 9 randomised, double-blind, placebo-controlled, short-term studies in adult outpatients with major depressive disorder. Pristiq demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score and the Clinical Global Impressions Scale-Improvement (CGI-I).
In a randomised withdrawal study, patients responding to 12 weeks of acute treatment with open-label Pristiq 200-400 mg once daily were randomised to either desvenlafaxine succinate or placebo for a further 6 months. Pristiq demonstrated significantly longer times to relapse of major depressive disorder than subjects receiving placebo during the double-blind phase of the study (p<0.0001). The incidence of relapse during the 6 months double-blind follow-up period was 24% and 42% for Pristiq and placebo, respectively.
Vasomotor Symptoms Associated with Menopause Studies: The efficacy of desvenlafaxine succinate in the treatment of vasomotor symptoms is thought to be related to the potentiation of the neurotransmitters serotonin and norepinephrine in the central nervous system. Desvenlafaxine succinate alleviated temperature dysfunction in hormone-depleted rodent models. In other preclinical rodent models, desvenlafaxine demonstrated activity predictive of antidepressant, and anxiolytic actions and pain inhibitory properties.
Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H₁-histaminergic or α₁-adrenergic receptors in vitro. Pristiq also lacked MAO inhibitory activity.
Pharmacokinetics: The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional over a dose range of 100-600 mg/day. The mean terminal half-life (t_1/2) is approximately 11 hrs. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4-5 days. At steady state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.
The pharmacokinetics of desvenlafaxine have been thoroughly evaluated in women and men. There are minimal differences based on gender.
Absorption and Distribution: Desvenlafaxine is well absorbed, with an absolute oral bioavailability of 80% [20% coefficient of variation (CV)]. Peak plasma concentrations (C_max) are observed between 7.5 hrs after oral administration. AUC and peak plasma concentrations of 6747 ng·hr/mL (23% CV) and 376 ng·hr/mL (23% CV), respectively, are predicted with once-daily administration of 100 mg.
Administration with food has minimal impact on drug absorption. Following administration with low, medium and high-fat meals, increases in C_max of approximately 16% were observed only following a high-fat meal. There was no change in AUC values for any of the meals. The plasma protein-binding of desvenlafaxine is low (30%) and is independent of drug concentration. Desvenlafaxine volume of distribution at steady state following IV 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 to the O-glucuronide, 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 P-450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine.
In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19 and 3A4 isozymes and does not induce CYP3A4 and other isozyme expressions. Desvenlafaxine is not a substrate for, or an inhibitor of, the P-glycoprotein transporter based on in vitro data.
Special Populations: Elderly: No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosage & Administration).
Pediatric: Safety and effectiveness in patients <18 years have not been established.
Hepatic: Desvenlafaxine 100 mg was studied kinetically in subjects with mild (Child-Pugh A, n=8), moderate (Child-Pugh B, n=8) and severe (Child-Pugh C, n=8) hepatic impairment and in healthy subjects (n=12).
Average AUC was increased by approximately 31% and 35% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. Average AUC values were comparable in subjects with mild hepatic impairment and healthy subjects (<5% difference).
Systemic clearance (CL/F) was decreased by approximately 20% and 36% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. CL/F values were comparable in mild hepatic impairment and healthy subjects (<5% difference).
The average t_1/2 changed from approximately 10 hrs in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hrs in moderate and severe hepatic impairment, respectively.
Renal: Desvenlafaxine 100 mg was studied kinetically in subjects with mild (n=9), moderate (n=8), severe (n=7) and end-stage renal disease (ESRD) requiring dialysis (n=9) and in healthy, age-matched control subjects (n=8). Elimination significantly correlated with creatinine clearance. Total body clearance was reduced in subjects with impaired renal function by 29% in mild, 39% in moderate, 51% in severe renal impairment (24-hr CrCl <30 mL/min), and 58% in ESRD, compared to normal subjects. This reduced clearance resulted in increases in AUCs of 42% in mild, 46% in moderate, 108% in severe and 116% in ESRD subjects.
The mean terminal half-life was prolonged from 11.1 hrs in the control subjects to 13.5, 15.5, 17.6 and 22.8 hrs in mild, moderate, severe renal impairment and ESRD subjects, respectively.
For patients with severe renal impairment (24-hr CrCl <30 mL/min) or ESRD, dosage adjustment is recommended (see Dosage & Administration).
Less than 5% of the drug in the body was cleared during a standard 4-hr hemodialysis procedure. Therefore, supplemental doses should not be given to patients after dialysis.