Single- and multiple-dose safety, tolerability and pharmacokinetics of a Novel 5HT6 receptor full antagonist (SAM-760) for the treatment of the symptoms of Alzheimer's disease in healthy young adults and elderly subjects

Abstract

Preclinical and preliminary clinical studies suggest that blocking 5 hydroxytrypamine receptors[5-HT6R] improves cognition and promotes synaptic plasticity by releasing acetylcholine and glutamate. Alzheimer's disease (AD) is partly characterized by deficits in these neurotransmitters. Antagonism of 5-HT6R, specifically brain localized, may result in less peripheral side effects than existing AD treatments. Ascending single oral doses 0.25-70 mg SAM-760 were administered to young subjects and multiple doses 1.5-30 mg and 10-20 mg to young and elderly subjects, respectively, using a randomized, double-blind, sponsor un-blinded, placebo-controlled, sequential dose study design. Additional cohorts in the SAD study included: elderly (10 mg SAM-760), food effect (10 mg SAM-760) and ketoconazole interaction (5 mg SAM-760; 400 mg ketoconazole). Study assessments consisted of safety, tolerability SAM-760 pharmacokinetics (plasma and urine). SAM-760 was safe and well tolerated as a single oral dose up to 70 mg in young subjects, at 10 mg in elderly and as multiple oral doses (QD 14 days) up to 30 mg and 20 mg in young and elderly subjects, respectively. There were no dose-limiting adverse events (AE). The most frequently reported treatment emergent AEs was headache. There were no subjects withdrawn for safety reasons, serious adverse events or deaths. SAM-760 exhibited dose proportional increases in Cmax and AUC0-INF for single doses up to 60 mg (young). Mean accumulation was 3.2-fold for AUC0-TAU and 2.7-fold for Cmax after 14-days of daily dosing, with approximate steady state exposure being reached following 7-days. SAM-760 elimination was similar in young and elderly subjects (t1/2 of approximately 32 hr) . Co-administration of ketoconazole with a single dose of SAM-760 increased AUC0-INF and Cmax, by 38% and 32%, respectively. There was no detectable PK food effect. SAM-760 was safe and well tolerated as a single and multiple oral dose over the dose ranges tested in healthy young and elderly subjects. SAM-760 exhibits linear PK for single doses up to 60 mg, with an accumulation of approximately 3-fold following multiple dose administration. SAM-760 elimination was comparable between healthy young and elderly subjects.