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

Abstract

AIMThe 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. METHODSSingle doses (0.1, 0.3,1,3,10, 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. RESULTSABT-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. CONCLUSIONSBased on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Histamine H3 receptor antagonists increase the release of the brain neurotransmitters that are known to modulate cognitive processes. H3 receptor antagonists have demonstrated pro-cognitive effects in preclinical studies. ABT-288 is a highly selective histamine H3 receptor antagonist designed for symptomatic treatment of cognitive disorders. WHAT THIS STUDY ADDS• In the present article, we present the safety, tolerability and pharmacokinetics of ABT-288 in healthy young adults and in elderly human subjects. Results from these trials, along with preclinical data, were the basis for advancing ABT-288 to proof-of-concept phase 2 evaluation in Alzheimer's disease and the presented studies guided dose selection for phase 2 testing. In general, results presented in the current article provide the most comprehensive characterization of the safety and tolerability profiles of pharmacological H3 receptor antagonism in young adults and elderly human subjects.

The H3antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers

“…and AUC ≥ 120 ng h ml −1 ) were clearly intolerable [14]. Dose-limiting effects appeared to be manifestations of excessive histamine, such as insomnia, abnormal dreams, hot flushes, nausea, dizziness, anxiety and palpitations.…”

“…The CSF samples were maintained on ice and stored in the freezer within 1 h after collection and maintained at −20°C or colder. Plasma concentrations of ABT-288 were determined using a validated protein precipitation extraction with highperformance liquid chromatography-tandem mass spectrometric detection at AbbVie (North Chicago, IL, USA) as described previously [14]. Cerebrospinal fluid concentrations of ABT-288 were determined using the same highperformance liquid chromatography-tandem mass spectrometric detection but with direct injection.…”

“…In humans, ABT-288 was previously evaluated in two phase 1 studies in healthy young adults and elderly volunteers [14]. The safety, tolerability and pharmacokinetics of ABT-288 were comparable in young and elderly subjects.…”

A Randomized Trial of the Efficacy and Safety of the H3 Antagonist ABT-288 in Cognitive Impairment Associated With Schizophrenia

“…19 Frequently reported adverse events such as abnormal dreams, insomnia, headache, and dizziness were similar to those observed in phase 1 studies of healthy volunteers and elderly subjects. 20 Subjects with schizophrenia in the phase 1 study tolerated higher daily doses and plasma exposures of ABT-288 than healthy adults and elderly subjects, where the maximum tolerated dose was 3 mg once daily. In subjects with schizophrenia, ABT-288 mean elimination half-life was 34-38 hours in the majority of evaluated dose groups.…”

Identification of the Antiarrhythmic Drugs Amiodarone and Lorcainide as Potent H3 Histamine Receptor Inverse Agonists

“…Compared with amiodarone, lorcainide distributes better to the brain (Klotz and Golbs, 1980) and lorcainide usage is associated with an increased prevalence of central nervous system effects, especially disturbed sleep (see Eiriksson and Brogden, 1984). Interestingly, insomnia is a reported side effect of H3 antagonists in humans (Herring et al, 2012;Othman et al, 2013), and H3 antagonists are in development as treatments for narcolepsy (Inocente et al, 2012). The H3 antagonist activity of lorcainide possibly contributes to its effects on sleep in humans.…”