Safety, tolerability, and pharmacokinetic evaluation of single‐ and multiple‐ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects

Stephen L. Lowe; Conrad J. Wong; Jennifer Witcher; Celedon R. Gonzales; Gemma L. Dickinson; Robert L. Bell; Linda Rorick‐Kehn; MaryAnn Weller; Randall R. Stoltz; Jane Royalty; Sitra Tauscher‐Wisniewski

doi:10.1002/jcph.286

journal article Mar 26, 2014

Safety, tolerability, and pharmacokinetic evaluation of single‐ and multiple‐ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects

Stephen L. Lowe Conrad J. Wong Jennifer Witcher Celedon R. Gonzales Gemma L. Dickinson Robert L. Bell Linda Rorick‐Kehn MaryAnn Weller Randall R. Stoltz Jane Royalty Sitra Tauscher‐Wisniewski

The Journal of Clinical Pharmacology Vol. 54 No. 9 pp. 968-978 · Wiley

View at Publisher Save 10.1002/jcph.286

Abstract

AbstractAccumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high‐affinity, selective kappa opioid antagonist that demonstrates >30‐fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2–60 mg), multiple oral doses (2, 10, and 35 mg), and when co‐administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography‐tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well‐tolerated with no clinically significant findings. No safety concerns were seen on co‐administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive‐motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half‐life of approximately 30–40 hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6–8 days of once‐daily dosing. Steady‐state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax) or AUC of ethanol (in the presence of LY2456302) were observed.

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Details

Published: Mar 26, 2014
Vol/Issue: 54(9)
Pages: 968-978
License: View

Authors

S

Stephen L. Lowe

Lilly‐NUS Centre for Clinical Pharmacology National University of Singapore Singapore Singapore

C

Conrad J. Wong

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

J

Jennifer Witcher

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

C

Celedon R. Gonzales

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

G

Gemma L. Dickinson

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

R

Robert L. Bell

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

L

Linda Rorick‐Kehn

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

M

MaryAnn Weller

inVentiv Health Clinical Ann Arbor MI USA

R

Randall R. Stoltz

Covance Clinical Research Unit, Inc. Evansville IN USA

J

Jane Royalty

Covance Clinical Research Unit, Inc. Evansville IN USA

S

Sitra Tauscher‐Wisniewski

Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

Funding

Eli Llly and Company

Cite This Article

Stephen L. Lowe, Conrad J. Wong, Jennifer Witcher, et al. (2014). Safety, tolerability, and pharmacokinetic evaluation of single‐ and multiple‐ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects. The Journal of Clinical Pharmacology, 54(9), 968-978. https://doi.org/10.1002/jcph.286

Safety, tolerability, and pharmacokinetic evaluation of single‐ and multiple‐ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects

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