Effect of Hepatic Impairment on the Pharmacokinetics of Levomilnacipran Following a Single Oral Dose of a Levomilnacipran Extended-Release Capsule in Human Participants

• Published in: Clinical drug investigation Vol. 34; no. 5; pp. 351 - 359
• Main Authors: Chen, Laishun, Boinpally, Ramesh, Greenberg, William M., Wangsa, Julie, Periclou, Antonia, Ghahramani, Parviz
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2014; Springer Nature B.V
• Subjects: Administration, Oral; Adolescent; Adult; Aged; Capsules; Case-Control Studies; Cyclopropanes - administration & dosage; Cyclopropanes - pharmacokinetics; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Internal Medicine; Liver Diseases - physiopathology; Male; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Young Adult; Healthy Participant; Milnacipran; Hepatic Impairment; Major Depressive Disorder
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-014-0182-5

Background and Objectives Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with greater potency for the reuptake inhibition of norepinephrine than of serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. Methods A single-dose, open-label, parallel-group study was conducted to evaluate the effects of hepatic impairment on the pharmacokinetics of levomilnacipran in adults with mild, moderate, or severe hepatic impairment and normal controls receiving a 40 mg levomilnacipran extended-release (ER) capsule. The concentrations of levomilnacipran and its inactive metabolite, N -desethyl levomilnacipran, in plasma and urine were measured using liquid chromatography–tandem mass spectrometry methods. Pharmacokinetic parameters of levomilnacipran and N -desethyl levomilnacipran were derived and assessed. Safety parameters were assessed throughout the trial. Results No deaths, serious adverse events, or discontinuations due to adverse events occurred. The maximum plasma drug concentration ( C max ) and area under the plasma concentration–time curve from time zero to infinity (AUC ∞ ) of levomilnacipran were 28 and 32 % higher, respectively, in participants with severe hepatic impairment than in healthy participants without a notable change in the t ½ , whereas the C max and AUC ∞ of N -desethyl levomilnacipran were 66 and 85 % lower, respectively, suggesting liver function has minimal impact on the overall exposure of levomilnacipran but plays a significant role in the formation of the metabolite. Conclusions A single dose of levomilnacipran ER 40 mg was generally well-tolerated in participants with varying degrees of hepatic impairment and healthy controls. Therefore, dose adjustment for levomilnacipran is not necessary in adult MDD patients with impaired liver function.