Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects. (October 2016)

• Record Type: Journal Article
• Authors: Spiegelstein, Ofer; Stevens, Jasper; Van Gerven, Joop; Nathan, Pradeep J; Maynard, James P; Mayleben, David W; Hellriegel, Edward; Yang, Ronghua
• Is Part Of: Journal of psychopharmacology. Volume 30:Number 10(2016:Oct.)
• Page Start: 983
• Page End: 993
• Publication Date: 2016-10
• Subjects: Pharmacokinetics and drug metabolism -- pharmacodynamics (PDY) -- population pharmacokinetics -- central nervous system (CNS) -- clinical trials (CTR) -- histamine-3 receptor antagonist; Psychopharmacology -- Periodicals; 615.78
• DOI: 10.1177/0269881116645301
• Languages: English
• ISSNs: 0269-8811

Abstract

CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3 R) 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 t max 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.