Action And Clinical Pharmacology
Mechanism of Action
Desvenlafaxine is the major active metabolite of venlafaxine which is also approved for treatment of depression. Preclinical studies have shown that desvenlafaxine succinate is a selective serotonin and norepinephrine reuptake inhibitor. The clinical efficacy of desvenlafaxine succinate 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. 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.
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, t1/2, is approximately 11 hours. 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; data from all subjects are presented below.
Absorption and Distribution:
The absolute oral bioavailability of PRISTIQ after oral administration is about 80%. Mean time to peak plasma concentrations (tmax) is about 7.5 hours after oral administration.
A food-effect study involving administration of PRISTIQ to healthy volunteers 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, PRISTIQ 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 Excretion:
Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine.
Residual Inert Matrix Tablet
Patients receiving PRISTIQ may notice an inert matrix tablet passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.
Special Populations and Conditions
In a trial of healthy subjects administered doses up to of 300 mg, women had an approximately 25% higher Cmax and an approximately 10% higher AUC than age-matched men. No adjustment of dosage on the basis of gender is needed.
PRISTIQ is not indicated for use in children and adolescents. Two placebo controlled phase 3 studies in 587 pediatric patients 7 to 17 years of age with MDD failed to demonstrate efficacy; neither short term, placebo-controlled study demonstrated statistically or clinically significant differences between PRISTIQ and placebo.
In a phase 2, 8-week open-label pharmacokinetic, safety, and tolerability study in 59 pediatric patients with MDD, PRISTIQ 10, 25, 50, and 100 mg was administered to 29 children (7 to 11 years old) and PRISTIQ 25, 50 100, and 200 mg was administered to 30 adolescents (12 to 17 years old). Mean CL/F (apparent oral dose clearance) values were higher in children (range: 0.441 to 0.540 L/h/kg) than values obtained in 397 adults (mean ± SD: [0.31± 0.15 L/h/kg]). Mean CL/F values for adolescents (range: 0.282 to 0.441 L/hr/kg)) were more comparable to CL/F values in adults. The effect of body weight on dose normalized AUC could be described by an exponential equation for each age group. Comparison of the predictions for AUC (normalized by dose) based on age and body weight or based only on body weight showed that body weight alone provides an adequate prediction for AUC. Mean urinary recovery of total desvenlafaxine and total N,O-didesmethylvenlafaxine ranged from 40% to 61% in children and 55 to 69% in adolescents. The pharmacokinetic results in pediatric patients from this study and the comparison with adults should be considered preliminary.
Twenty children and 20 adolescents who completed the pharmacokinetics study entered a 6-month, open-label, phase 2 extension safety study. The total daily dose of PRISTIQ was flexible between 10, 25, 50, and 100 mg for children, and between 25, 50, 100, and 200 mg for adolescents. Eighteen subjects (45%) completed the extension study.
In both studies combined, 28 subjects (70%) reported 1 or more treatment-emergent adverse event (TEAE). Four (20.0%) children and 3 (15.0%) adolescents reported adverse events that led to discontinuation of treatment: aggression (by 2 children), disturbance in attention and psychomotor hyperactivity (by 1 child), negativism (by 1 child) and nausea (by 1 adolescent), nausea and headache (by 1 adolescent), and pregnancy (by 1 adolescent). For children, the most common TEAEs during the on-therapy period of both studies combined were headache and abdominal pain reported by 3 (15.0%) and 3 (15.0%) of patients, respectively. For adolescents, the most common TEAEs during the on-therapy period of both studies combined were: somnolence, nausea, headache, and abdominal pain upper, reported by 6 (30.0%), 4 (20.0%), 3 (15.0%) and 3 (15.0%) of subjects, respectively. In addition, for child and adolescent subjects in the combined study population, post-baseline suicidal ideation occurred in 3 adolescents, as assessed via the Columbia Suicide Severity Rating Scale (C-SSRS). Suicidal ideation was reported in 1 adolescent subject who did not report suicidal ideation at the baseline C-SSRS assessment (the baseline C-SSRS assessment was the screening visit of the pharmacokinetic study) (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).
In a trial of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in Cmax and a 55% increase in AUC in subjects older than 75 years of age (n =17), compared with subjects 18 to 45 years of age (n = 16). Subjects 65 to 75 years of age (n =15) had no change in Cmax but an approximately 32% increase in AUC, compared to 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.
Pharmacokinetic analysis on the basis of race (White, N = 466; Black, N = 97; Hispanic, N = 39; Other, N =33) did not demonstrate an effect on the pharmacokinetics of PRISTIQ. No adjustment of dosage on the basis of race is needed.
The disposition of desvenlafaxine succinate after administration of 100 mg was 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 to 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 similar 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 t1/2 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. No dosage adjustment is necessary for patients with hepatic impairment.
The disposition of desvenlafaxine after administration of 100 mg was 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. Increases in AUCs of about 42% in mild renal impairment, about 56% in moderate renal impairment, about 108% in severe renal impairment, and about 116% in ESRD subjects were observed, compared with healthy, age-matched, control subjects.
The mean terminal half-life (t1/2) was prolonged from 11.1 hours in the control subjects to approximately 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 AND ADMINISTRATION, Patients with severe renal impairment and end-stage renal disease).