The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers

Abstract

Aims: ABT-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.

Methods: This 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.

Results: Of 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.

Conclusions: ABT-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.

Keywords: ABT-288; cognitive deficits; histamine H3 receptors; schizophrenia; tolerability.

© 2013 The British Pharmacological Society.

Figures

Figure 1

Mean ABT-288 plasma concentration vs. time profiles after administration of escalating multiple once-daily oral doses to subjects with schizophrenia. , 1 mg; , 3 mg; , 6 mg; , 9 mg; , 12 mg; , 15 mg; , 20 mg; , 30 mg; , 45 mg; , 60 mg

Figure 2

Dose-normalized maximal observed ABT-288 plasma concentration (Cmax; A; , day 1; , day 14) and area under the plasma concentration–time curve (AUC; B; , day 1; , day 14) values (mean ± SD) vs. dose plots