1. Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects.
- Author
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Spiegelstein O, Stevens J, Van Gerven J, Nathan PJ, Maynard JP, Mayleben DW, Hellriegel E, and Yang R
- Subjects
- Administration, Oral, Adolescent, Adult, Double-Blind Method, Female, Half-Life, Healthy Volunteers, Humans, Male, Nootropic Agents pharmacokinetics, Nootropic Agents therapeutic use, Pyridazines blood, Pyridazines urine, Pyrrolidines blood, Pyrrolidines urine, Young Adult, Histamine metabolism, Histamine Antagonists pharmacokinetics, Histamine Antagonists therapeutic use, Pyridazines pharmacokinetics, Pyridazines therapeutic use, Pyrrolidines pharmacokinetics, Pyrrolidines therapeutic use, Receptors, Histamine metabolism
- 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., (© The Author(s) 2016.)
- Published
- 2016
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