Document Detail

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.
MedLine Citation:
PMID:  23016924     Owner:  NLM     Status:  MEDLINE    
AIM: The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting.
METHODS: Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design.
RESULTS: ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure.
CONCLUSIONS: Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients.
Ahmed A Othman; George Haig; Hana Florian; Charles Locke; Jun Zhang; Sandeep Dutta
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  75     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-08     Completed Date:  2013-10-01     Revised Date:  2014-05-08    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1299-311     Citation Subset:  IM    
Copyright Information:
© 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Administration, Oral
Alzheimer Disease / drug therapy*,  metabolism
Dose-Response Relationship, Drug
Double-Blind Method
Histamine H3 Antagonists / adverse effects*,  pharmacokinetics*
Pyridazines / adverse effects*,  pharmacokinetics*
Pyrroles / adverse effects*,  pharmacokinetics*
Young Adult
Reg. No./Substance:
0/2-(4'-(5-methylhexahydropyrrolo(3,4-b)pyrrol-1-yl)biphenyl-4-yl)-2H-pyridazin-3-one; 0/Histamine H3 Antagonists; 0/Pyridazines; 0/Pyrroles

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