title: Multiple-dose safety, pharmacokinetics, and pharmacodynamics of the μ-opioid receptor inverse agonist GSK1521498.
abstract: The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.
authors.affiliation: GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2GG UK. pradeep.j.nathan@gsk.com
authors.forename: Pradeep J
authors.initials: PJ
authors.lastname: Nathan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bush
authors.forename: Wenli X
authors.initials: WX
authors.lastname: Tao
authors.forename: Annelize
authors.initials: A
authors.lastname: Koch
authors.forename: Kirsty M
authors.initials: KM
authors.lastname: Davies
authors.forename: Kay
authors.initials: K
authors.lastname: Maltby
authors.forename: Barry V
authors.initials: BV
authors.lastname: O'Neill
authors.forename: Antonella
authors.initials: A
authors.lastname: Napolitano
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Skeggs
authors.forename: Allison C
authors.initials: AC
authors.lastname: Brooke
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Richards
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Williams
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006358:Hot Temperature; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D017288:Pain Threshold / Q000187:drug effects; D011312:Pressure; D017450:Receptors, Opioid, mu / Q000819:agonists*; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D007189:Indans; C568078:N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine; D017450:Receptors, Opioid, mu; D014230:Triazoles