Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects

Abstract

CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.

Central nervous system effects of the histamine‐3 receptor antagonist CEP‐26401, in comparison with modafinil and donepezil, after a single dose in a cross‐over study in healthy volunteers

“…CEP‐26401 dose levels were determined based on clinical findings from the 2 completed clinical studies with CEP‐26401 and PK/PD modelling . A dose of 20 μg was anticipated to have the largest cognition‐enhancing effect in a subset of Cambridge Neuropsychological Test Automated Battery (CANTAB) tests.…”

“…During study periods, safety was monitored based on adverse events (AEs), ocular pressure measurement, vital signs, ECG, safety chemistry and haematology blood sampling, urinalysis, physical examination and concomitant medication usage. In previous studies, CEP‐26401 has been administered to healthy volunteers in doses up to 5 mg . In these studies, intraocular pressure emerged as a safety finding of possible concern.…”

“…Prestudy power calculations were based on the effects of CEP‐26401 on between errors of the SWM task with 10 boxes, in previous studies with CEP‐26401 in healthy volunteers and PK/PD‐modelling of this data . In the study reported in this manuscript, 24 subjects were planned to have a cross‐over comparison between CEP‐26401 5, 25 or 125 μg and placebo.…”

“…CEP‐26401 ([6‐[4‐[3‐[(2R)‐2‐methyl‐1‐pyrrolidinyl]propoxy]phenyl]‐3‐(2H)‐pyridazinone hydrochloride]) is an H 3 R antagonist/inverse agonist that displays high‐affinity H 3 R binding and potent functional antagonism in both rat and human recombinant cell and native rat brain cortical systems . Two clinical studies with orally administered single and multiple doses of CEP‐26401 in healthy volunteers have been performed prior to this study with interesting results on the spatial working memory (SWM) task . In this task, several boxes are presented on the screen, in 1 of which a token is to be found.…”

“…Although data were derived from 2 different studies with parallel‐group designs, where differences between groups and study design may have played a role (i.e. studies were not powered nor specifically designed to detect differences in cognition enhancement), the PK/PD‐model based on these studies consistently indicated the largest cognitive effects at the lowest dose . It was therefore of interest to investigate the dose–response relationship of CEP‐26401 on cognition at a dose range below as well as above 20 μg.…”