title: Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.
abstract: OBJECTIVE
  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.
authors.affiliation: Abbott Clinical Pharmacology and Pharmacometrics, Abbott Laboratories, Abbott Park, IL 60064, USA. ahmed.othman@abbott.com
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Othman
authors.forename: George
authors.initials: G
authors.lastname: Haig
authors.forename: Hana
authors.initials: H
authors.lastname: Florian
authors.forename: Charles
authors.initials: C
authors.lastname: Locke
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D054828:Histamine H3 Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D011724:Pyridazines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C576396:2-(4'-(5-methylhexahydropyrrolo(3,4-b)pyrrol-1-yl)biphenyl-4-yl)-2H-pyridazin-3-one; D054828:Histamine H3 Antagonists; D011724:Pyridazines; D011758:Pyrroles