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

Abstract

AIMSABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. METHODSThis was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. RESULTSOf the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. CONCLUSIONSABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake.

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

“…18 In a phase 1 multiple dose study of subjects with schizophrenia, doses of ABT-288 up to 60 mg once daily were administered and doses up to 45 mg once daily were safe and well tolerated. 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.…”

“…An increase in psychosis-related events were observed in the phase 1 study in subjects with schizophrenia, but the inflection point appeared to occur at doses greater than those used in this study. 19 Higher rates of psychosis were not reported in previous schizophrenia studies with H3 antagonists. 16,17 However, doses in all of these trials were comparable to those used in other populations, not the 10-fold increase administered in this study.…”

“…This is consistent with observations from our phase 1 studies and reports of other H3 antagonists 16,17 and is not unexpected given the release of the pro-wake neurotransmitter histamine that is central to the mechanism of H3 antagonists. 19 This study was designed largely in accordance with the MATRICS guidelines, and several lines of evidence suggest the hypothesis was adequately tested. The overall subject completion rate of 80.3% was comparable to other trials of CIAS in clinically stable patients.…”

“…In subjects with schizophrenia, ABT-288 mean elimination half-life was 34-38 hours in the majority of evaluated dose groups. 19 The objective of this study was to assess the efficacy and safety of ABT-288 when added to an antipsychotic regimen for 12 weeks (84 d) in treating cognitive impairment in clinically stable subjects with schizophrenia. The doses selected for this study were the highest well-tolerated dose from phase 1 (ABT-288 25 mg once daily) and a lower dose (10 mg once daily) that provided plasma exposures covering the efficacious levels in preclinical models of cognition.…”

The Role of Tau Protein in Diseases

“…Hence working on this hypothesis two drugs were introduced, such as ABT-288 and GSK239512 (Scheme 4). The phase I and phase II clinical trials of the former one have shown tremendous anti-AD activity while the later drug has not shown any considerable progress in low-moderate AD patients [70][71][72][73].…”