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

Abstract

Accumulating 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.

Receptor Occupancy of the -Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

“…after drug administration for determination of plasma concentration of LY2456302 by liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the lower limit of quantification at 0.20 ng/mL, as described previously (Lowe et al, 2014). Image Acquisition.…”

“…The primary aim of this study was to demonstrate brain penetration and KOR target engagement after single oral doses of LY2456302 in healthy human subjects. KOR occupancy was assessed using the KOR specific antagonist radiotracer 11 C-LY2795050 Naganawa et al, 2014Naganawa et al, , 2015 and positron emission tomography (PET) across a range of doses (0.5-25 mg) that have been demonstrated to be safe and well tolerated in a previous study (Lowe et al, 2014). We measured RO at multiple doses and postdosing times, and characterized the relationship between LY2456302 plasma concentrations and KOR occupancy.…”

Dynorphin, Dysphoria, and Dependence: the Stress of Addiction

“…However, very exciting preclinical findings too often fail to deliver on their promises, particularly in CNS drug development, which is notoriously expensive and difficult. Progress is being made with a kappa antagonist (LY2456302) developed by Eli Lilly scientists, which passed initial safety testing and has been licensed for development by Cerecor (Lowe et al, 2014). Another key to this translational effort will be the further development of selective kappa opioid PET imaging in normal and affected human subjects, which is still at a nascent stage.…”

Major Depressive Disorder and Kappa Opioid Receptor

“…[105] CERC-501 has rapid absorption (t max : 1-2 h) and good oral bioavailability (F = 25%). [106] In clinical trials, CERC-501 displayed rapid oral absorption and a terminal half-life of approximately 30-40 hours in healthy subjects [107] . Plasma exposure of CERC-501 increased proportionally with increasing doses and reached steady state after 6-8 days for once-daily dosing [107] .…”