title: 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.
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lowe
authors.forename: Conrad J
authors.initials: CJ
authors.lastname: Wong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Witcher
authors.forename: Celedon R
authors.initials: CR
authors.lastname: Gonzales
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Dickinson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bell
authors.forename: Linda
authors.initials: L
authors.lastname: Rorick-Kehn
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Weller
authors.forename: Randall R
authors.initials: RR
authors.lastname: Stoltz
authors.forename: Jane
authors.initials: J
authors.lastname: Royalty
authors.forename: Sitra
authors.initials: S
authors.lastname: Tauscher-Wisniewski
mesh_terms: D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000428:Alcohol Drinking; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004856:Postural Balance / Q000187:drug effects; D011388:Prolactin / Q000097:blood; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011930:Reaction Time / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D000431:Ethanol; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D007986:Luteinizing Hormone; C000590915:Aticaprant; D006854:Hydrocortisone
keywords: LY2456302; dynorphin; kappa opioid receptor