title: Levomilnacipran Pharmacokinetics in Healthy Volunteers Versus Patients with Major Depressive Disorder and Implications for Norepinephrine and Serotonin Reuptake Inhibition.
abstract: OBJECTIVE
  Levomilnacipran, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is approved for the treatment of major depressive disorder (MDD) in adults. The objectives of this investigation were to characterize the pharmacokinetic (PK) parameters of levomilnacipran in healthy subjects and in patients with MDD and to compare the plasma concentrations observed at clinically effective doses (40-120 mg daily) in MDD patients versus in vitro inhibitory concentration values for NE and 5-HT transporters.
  
  
  METHODS
  Data from 2 trials were analyzed: a Phase I trial (healthy volunteers received a single dose of levomilnacipran extended-release capsule [ER; 25, 50, or 100 mg], escalating multiple doses of levomilnacipran ER [25-300 mg once daily], or placebo); and a Phase III trial (adults with MDD received a fixed dose of levomilnacipran ER [40, 80, or 120 mg once daily for 8 weeks]). Plasma samples of participants were assayed to determine levomilnacipran concentrations, and PK analyses were performed. Unbound plasma concentrations of levomilnacipran in MDD patients were estimated, and inhibitory concentration values were determined by curve fitting of the in vitro data.
  
  
  RESULTS
  Cmax and AUC were dose proportional after single dosing (25-100 mg) and multiple dosing (across the 25-300 mg dose range) of levomilnacipran ER in healthy subjects. Dose-proportional steady-state Cmax (93, 180, and 297 ng/mL) and AUC0-τ (1520, 2935, and 4799 ng*h/mL) were also observed in patients with MDD who received levomilnacipran ER (40, 80, and 120 mg daily). Tmax was ~6 hours and was similar after single and multiple oral doses of levomilnacipran ER. Estimates of levomilnacipran concentration at 50%, 80%, and 90% inhibition were 19, 91, and 237 nM, respectively, for the 5-HT transporter, and 10, 41, and 92 nM for the NE transporter. Average unbound plasma concentrations for levomilnacipran in MDD patients treated with levomilnacipran ER 40, 80, or 120 mg daily exceeded the estimated concentration at 80% and 90% inhibition for 5-HT and NE.
  
  
  CONCLUSIONS
  Levomilnacipran PK was dose proportional after single and multiple dosing and was similar between healthy subjects and patients with MDD. Steady-state unbound plasma concentrations of levomilnacipran across the approved dose range (40, 80, and 120 mg daily) in MDD patients were estimated to be comparable or greater than the concentrations that inhibited reuptake of NE and 5-HT by >90% and >80%, respectively, in vitro.
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey. Electronic address: laishun.chen@actavis.com.
authors.forename: Laishun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey.
authors.forename: William M
authors.initials: WM
authors.lastname: Greenberg
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey.
authors.forename: Carl
authors.initials: C
authors.lastname: Gommoll
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey.
authors.forename: Joann
authors.initials: J
authors.lastname: O'Connor
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Zukin
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey.
authors.forename: Antonia
authors.initials: A
authors.lastname: Periclou
authors.affiliation: Forest Research Institute, Inc, an affiliate of Actavis Inc, Jersey City, New Jersey.
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghahramani
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D000078764:Milnacipran; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D003521:Cyclopropanes; D003692:Delayed-Action Preparations; D000078764:Milnacipran; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: SNRI; levomilnacipran; major depressive disorder; pharmacokinetics; transporter inhibition