Pharmacology: Mode of Action: Non-clinical trials have 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.
In preclinical rodent models, desvenlafaxine demonstrated activity predictive of antidepressant, anxiolytic and thermoregulatory actions, and pain inhibitory properties.
Pharmacodynamics: Clinical Efficacy: The efficacy of desvenlafaxine as a treatment for depression was established in four, 8-week, randomized, double-blind, placebo-controlled, fixed-dose trials and two relapse prevention trials in adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder. In the first trial, patients received 100 mg (n = 114), 200 mg (n = 116), or 400 mg (n = 113) of desvenlafaxine once daily, or placebo (n = 118). In a second trial, patients received either 200 mg (n = 121) or 400 mg (n = 124) of desvenlafaxine once daily, or placebo (n = 124). In two additional trials, patients received 50 mg (n = 150 and n = 164) or 100 mg (n = 147 and n = 158) of desvenlafaxine once daily, or placebo (n = 150 and n = 161).
Desvenlafaxine showed superiority over placebo as measured by improvement in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score in four trials and, as measured by the Clinical Global Impressions Scale-Improvement (CGI-I), in three of the four trials. There was no clear evidence that doses greater than 50 mg/day conferred any additional benefit.
In a long-term trial, adult outpatients meeting DSM-IV criteria for major depressive disorder, who responded to 8 weeks of open-label acute treatment with 50 mg/day desvenlafaxine and subsequently remained stable for 12 weeks on desvenlafaxine, were assigned randomly in a double-blind manner to remain on active treatment or switch to placebo for up to 26 weeks of observation for relapse. Response during the open phase was defined as a HAM-D17 total score of ≤11 and CGI-I ≤2 at the day 56 evaluation; stability was defined as not having a HAM-D17 total score of ≥16 at any office visit. Relapse during the double-blind phase was defined as follows: (1) a HAM-D17 total score of ≥16 at any office visit, (2) discontinuation for unsatisfactory efficacy response, (3) hospitalized for depression, (4) suicide attempt, or (5) suicide. Patients receiving continued desvenlafaxine treatment experienced statistically significantly longer time to relapse compared with placebo. At 26 weeks, the Kaplan-Meier estimated probability of relapse was 14% with desvenlafaxine treatment versus 30% with placebo.
In a second long-term trial, adult outpatients meeting DSM-IV criteria for MDD and who responded to 12 weeks of acute treatment with desvenlafaxine were assigned randomly to the same dose (200 or 400 mg/day) they had received during acute treatment or to placebo for up to 26 weeks of observation for relapse. Response during the open phase was defined as a HAM-D17 total score of ≤11 at the day 84 evaluation. Relapse during the double-blind phase was defined as follows: (1) a HAM-D17 total score of ≥16 at any office visit, (2) a CGI-I score of ≥6 (versus day 84) at any office visit, or (3) discontinuation from the trial due to unsatisfactory response. Patients receiving continued desvenlafaxine treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.
Analyses of the relationships between treatment outcome and age and treatment outcome and gender did not suggest any differential responsiveness on the basis of these patient characteristics. There was insufficient information to determine the effect of race on outcome in these trials.
Pediatric: The PRISTIQ pediatric development program investigated the acute treatment of MDD in pediatric patients (ages 7 to 17) and consisted of 6 studies: 2 Phase 2 studies (Study 3151A6-2000-US hereafter referred to as B2061012, and its 26-week open-label extension (OLE) Study 3151A6-2001-US here-after referred to as B2061013), and 4 Phase 3 studies (8-week Studies B2061014 and B2061032 hereafter referred to as the placebo-controlled studies, and their respective 26 week OLE Studies B2061031 and B2061030). A total of 761 subjects were evaluated across the clinical development program, of which 684 unique patients received DVS SR in at least one of the 6 studies.
The results of the two placebo-controlled studies showed no statistically significant difference between placebo and PRISTIQ for the pre-defined primary endpoint [change from baseline to Week 8 in the Children's Depression Rating Scale - Revised (CDRS-R)]. There was no relationship between desvenlafaxine exposure and change from baseline to Week 8 CDRS-R total score.
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 (t½), 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.
The pharmacokinetics of desvenlafaxine have been thoroughly evaluated in women and men. There are minimal differences based on gender; data from all subjects are presented as follows.
Absorption and distribution: Desvenlafaxine succinate is well absorbed, with an absolute oral bioavailability of 80%. Mean time to peak plasma concentrations (Tmax) is about 7.5 hours after oral administration. AUC and Cmax of 6,747 ng·hr/mL and 376 ng/mL, respectively, are observed after multiple doses of 100 mg.
Effects of food: A food-effect trial involving administration of desvenlafaxine to healthy subjects under fasting and fed conditions (high-fat meal) indicated that the Cmax 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's 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: In a trial of healthy subjects administered doses up to 300 mg, there was an age-dependent decrease in desvenlafaxine clearance, resulting in a 32% increase in Cmax and a 55% increase in AUC values in subjects greater than 75 years of age, as compared with subjects 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 (see DOSAGE & ADMINISTRATION).
Patients with renal impairment: The pharmacokinetics of desvenlafaxine succinate 100 mg were studied 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 was significantly correlated with creatinine clearance. Total body clearance was reduced by 29% in mild, 39% in moderate, 51% in severe renal impairment and 58% in ESRD compared to healthy subjects. This reduced clearance resulted in increases in AUCs of 42% in mild (24-hr CrCl = 50-80 mL/min), 56% in moderate (24-hr CrCl = 30-50 mL/min), 108% in severe (24-hr CrCl < 30 mL/min), and 116% in ESRD subjects.
The mean terminal half-life (t½) was prolonged from 11.1 hours in the healthy subjects to 13.5, 15.5, 17.6, and 22.8 hours in mild, moderate, severe renal impairment and ESRD subjects, respectively.
Less than 5% of the drug in the body was cleared during a standard 4-hour hemodialysis procedure. Therefore, supplemental doses should not be given to patients after dialysis. Dosage adjustment is recommended in patients with significant impairment of renal function (see DOSAGE & ADMINISTRATION).
Patients with hepatic impairment: The pharmacokinetics of desvenlafaxine succinate 100 mg were studied 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 mean t½ changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively (see DOSAGE & ADMINISTRATION).
Thorough QTc trial: In a thorough QTc trial with prospectively determined criteria, in healthy women, desvenlafaxine did not cause QT prolongation. Additionally, no effect on QRS interval was observed.
Toxicology: Preclinical safety data: Carcinogenicity: Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either trial.
Mice received desvenlafaxine at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The 300 mg/kg/day dose is 90 times, on a mg/kg basis, the maximum recommended human dose (MRHD) of 200 mg/day, and 7 times the MRHD, on a mg/m2 basis.
Rats received desvenlafaxine at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The highest dose was 90 (males) or 150 (females) times, on a mg/kg basis, the MRHD of 200 mg/day, and 15 (males) or 24 (females) times the MRHD of 200 mg/day, on a mg/m2 basis.
Mutagenicity: Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay.
Impairment of fertility: Reduced fertility was observed in a preclinical trial in which both male and female rats received desvenlafaxine succinate.
This effect was noted at oral doses approximately 30 times, on a mg/kg basis, and 5 times the maximum human dose (MRHD) of 200 mg/day on a mg/m2 basis. There was no effect on fertility at oral doses approximately 9 times the MRHD on a mg/kg basis, and 1.5 times the MRHD on a mg/m2 basis. The human relevance of this finding is unknown.
Teratogenicity: When desvenlafaxine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity in rats at any doses tested, up to 30 times on a mg/kg basis and up to 5 times the maximum recommended human dose (MRHD) of 200 mg/day (on a mg/m2 basis) in rats, In rabbits, there was no evidence of teratogenicity at doses up to 23 times (on a mg/kg basis) the MRHD of 200 mg/day, or 7 times the MRHD (on a mg/m2 basis). However, fetal weights were decreased in rats with a no-effect dose 30 times the MRHD (on a mg/kg basis) 5 times the MRHD (on a mg/m2 basis).
When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was a decrease in pup weights and increase in pup deaths during the first four days of lactation. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 30 times on a mg/kg basis and 5 times the MRHD of 200 mg/day (on a mg/m2 basis). Post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine at a dose 90 times the MRHD (on a mg/kg basis) and 15 times the MRHD (on a mg/m2 basis).