Pharmacokinetics and pharmacodynamics of edivoxetine (LY2216684), a norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder.

Abstract

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 ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-∞)) 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 ∼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.

• Authors: William Kielbasa, Tonya Quinlan, Ling Jin, Wen Xu, D Richard Lachno, Robert A Dean, Albert J Allen
• Journal: Journal of child and adolescent psychopharmacology (J Child Adolesc Psychopharmacol) Vol. 22 Issue 4 Pg. 269-76 (Aug 2012) ISSN: 1557-8992 [Electronic] United States
• PMID: 22849510 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic Uptake Inhibitors
• Morpholines
• alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol
• Phenylethyl Alcohol

Topics

• Administration, Oral
• Adolescent
• Adrenergic Uptake Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Age Factors
• Area Under Curve
• Attention Deficit Disorder with Hyperactivity (drug therapy)
• Child
• Chromatography, Liquid
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Humans
• Male
• Morpholines (administration & dosage, pharmacokinetics, pharmacology)
• Phenylethyl Alcohol (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Tandem Mass Spectrometry
• Tissue Distribution