Pharmacokinetics and Pharmacodynamics of Edivoxetine (LY2216684), a Norepinephrine Reuptake Inhibitor, in Pediatric Patients with Attention-Deficit/Hyperactivity Disorder

Objective: Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. Methods: During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Results: Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (t(max)) of edivoxetine was similar to 2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of similar to 6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C-max) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (V-ss/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of similar to 28%, most notably within 8 hours of edivoxetine administration. Conclusion: This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK-PD models to guide dosing strategies.