title: Effect of renal impairment on the pharmacokinetics of levomilnacipran following a single oral dose of levomilnacipran extended-release capsule in humans.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA.
authors.forename: Laishun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Greenberg
authors.affiliation: Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA.
authors.forename: Elimor
authors.initials: E
authors.lastname: Brand-Schieber
authors.affiliation: Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Wangsa
authors.affiliation: Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Periclou
authors.affiliation: Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA.
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghahramani
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D005260:Female; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007674:Kidney Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D000078764:Milnacipran; D065667:Renal Elimination; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D053719:Tandem Mass Spectrometry; D014481:United States
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D003692:Delayed-Action Preparations; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000078764:Milnacipran
keywords: F2695; SNRI; antidepressant; major depressive disorder; pharmacokinetics; renal function