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

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.

DOI: 10.1111/j.1365-2125.2012.04472.x

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