Effect of renal impairment on the pharmacokinetics of levomilnacipran following a single oral dose of levomilnacipran extended-release capsule in humans

• Published in: Drug design, development and therapy Vol. 9; pp. 3293 - 3300
• Main Authors: Chen, Laishun, Greenberg, William M, Brand-Schieber, Elimor, Wangsa, Julie, Periclou, Antonia, Ghahramani, Parviz
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2015; Taylor & Francis Ltd; Dove Press; Dove Medical Press
• Subjects: Administration, Oral; Adult; Aged; antidepressant; Antidepressants; Antidepressive Agents - administration & dosage; Antidepressive Agents - adverse effects; Antidepressive Agents - blood; Antidepressive Agents - pharmacokinetics; Area Under Curve; Bioavailability; Chemistry, Pharmaceutical; Chromatography, Liquid; Clinical trials; Cyclopropanes - administration & dosage; Cyclopropanes - adverse effects; Cyclopropanes - blood; Cyclopropanes - pharmacokinetics; Data analysis; Delayed-Action Preparations; Dose-response relationship (Biochemistry); Drug dosages; Drug metabolism; Electrocardiography; F2695; FDA approval; Female; Food; Half-Life; Humans; Impairment; Kidney - metabolism; Kidney - physiopathology; Kidney diseases; Kidney Diseases - diagnosis; Kidney Diseases - metabolism; Kidney Diseases - physiopathology; Laboratories; Liquid chromatography; major depressive disorder; Male; Mass spectrometry; Mass spectroscopy; Mental depression; Metabolic Clearance Rate; Metabolites; Middle Aged; Observations; Original Research; Pharmaceuticals; Pharmacokinetics; Pharmacology; Physiological aspects; Plasma; Plasma levels; Psychiatry; Radioactive half-life; Renal Elimination; Renal function; Research centers; Safety; Safety measures; Serotonin; Serotonin and Noradrenaline Reuptake Inhibitors - administration & dosage; Serotonin and Noradrenaline Reuptake Inhibitors - adverse effects; Serotonin and Noradrenaline Reuptake Inhibitors - blood; Serotonin and Noradrenaline Reuptake Inhibitors - pharmacokinetics; Severity of Illness Index; SNRI; Tandem Mass Spectrometry; United States; Urine; Variance analysis; United States; United States > US; pharmacokinetics; renal function; SNRI; major depressive disorder; F2695; antidepressant
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S85418

Levomilnacipran extended-release (ER) is indicated for treatment of major depressive disorder in adults. We evaluated the pharmacokinetic and safety profile of levomilnacipran ER in individuals with impaired renal function. A total of 32 individuals participated in four groups (eight in each group) with normal, mild, moderately, or severely impaired renal function. Each participant received one dose of levomilnacipran ER 40 mg. Blood and urine were assayed using liquid chromatography/tandem mass spectrometry. Results between normal and renally impaired groups were compared using analysis of variance. Safety measures included adverse events, laboratory evaluations, vital signs, suicidality, and electrocardiograms. Following administration of levomilnacipran, mean (standard deviation) maximum plasma concentration in participants with normal renal function, and mild, moderate, or severe renal impairment was 83.9 (21.0), 81.8 (23.4), 98.7 (18.1), and 122.1 (35.1) (ng/mL), respectively; area under the curve from time zero to infinity was 2,101.0 (516.9), 2,587.8 (649.9), 4,016.4 (995.4), and 5,900.8 (1,799.3) (h · ng/mL), respectively; terminal elimination half-life was 13.5 (2.8), 17.3 (3.5), 19.1 (4.6), and 27.7 (7.4) (hours), respectively; and renal clearance was 175.9 mL/min, 114.7 mL/min, 69.9 mL/min, and 28.6 mL/min, respectively. Levomilnacipran ER was generally well tolerated with no safety issues of concern identified. Renal impairment was associated with increased plasma levels of levomilnacipran and prolonged half-life. No dose adjustment is required for individuals with mild renal impairment; the recommended maximum daily maintenance dose of levomilnacipran ER should not exceed 80 mg for individuals with moderate renal impairment and 40 mg for individuals with severe renal impairment.