desvenlafaxine-succinate and Kidney-Failure--Chronic

Desvenlafaxine (administered as desvenlafaxine succinate), the major active metabolite of venlafaxine, is a new serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD).. To assess the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers vs. those with renal impairment.. A single, oral, 100 mg dose of desvenlafaxine was administered to healthy subjects (n = 8) and subjects with mild (n = 9), moderate (n = 9), or severe (n = 7) renal impairment (24-h creatinine clearance, ml/min: 50 - 80, 30 - 50, or < 30 ml/min, respectively) or end-stage renal disease (ESRD; on dialysis.

Topics: Adolescent; Adult; Aged; Area Under Curve; Cyclohexanols; Desvenlafaxine Succinate; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Stereoisomerism

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

Topics: Analysis of Variance; Cyclohexanols; Desvenlafaxine Succinate; Female; Humans; Kidney Failure, Chronic; Male; Neurotransmitter Uptake Inhibitors; Renal Dialysis; Venlafaxine Hydrochloride