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Clinical Trial
. 2013 May;75(5):1299-311.
doi: 10.1111/j.1365-2125.2012.04472.x.

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

Ahmed A Othman  1 , George Haig, Hana Florian, Charles Locke, Jun Zhang, Sandeep Dutta
Affiliations
Clinical Trial

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

Ahmed A Othman et al. Br J Clin Pharmacol. 2013 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Mean plasma concentrations (linear and log scales) vs. time profiles of ABT-288 after administration of escalating single oral doses to healthy young adults. •, 0.1 mg; ▵; 0.3 mg; ▪, 1 mg; ◊, 3 mg; ▾, 10 mg; ☆, 20 mg; ♦, 40 mg
Figure 2
Figure 2
Dose-normalized ABT-288 Cmax and AUC values (mean and SD) vs. dose plots following single dosing (A) or at steady-state (B). Cmax •, young adults; ○, elderly subjects; AUC ▴, young adults; ▿, elderly subjects
Figure 3
Figure 3
Mean plasma concentrations vs. time profiles of ABT-288 after administration of a single oral dose (5 mg) of ABT-288 under fasting and non-fasting (high fat/high calorie breakfast) conditions to healthy subjects. •, 5 mg, fasting; □, 5 mg, non-fasting
Figure 4
Figure 4
Mean plasma concentrations vs. time profiles of ABT-288 after administration of escalating once-daily oral doses of ABT-288 to healthy young adults. ▴, 0.5 mg once-daily; ◊, 1.5 mg once-daily; •, 3 mg once-daily; ▿, 6 mg once-daily
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