Levomilnacipran Pharmacokinetics in Healthy Volunteers Versus Patients with Major Depressive Disorder and Implications for Norepinephrine and Serotonin Reuptake Inhibition

Purpose: 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. Findings: C-max and AUG 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 C-max (93, 180, and 297 ng/mL) and AUC(0-tau) (1520, 2935, and 4799 ng*h/mL) were also observed in patients with MDD who received levomilnacipran ER (40, 80, and 120 mg daily). T-max was similar to 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 levomanacipran ER 40, 80, or 120 mg daily exceeded the estimated concentration at 80% and 90% inhibition for 5-HT and NE. (C) 2015 Elsevier HS Journals, Inc. All rights reserved.