title: 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.
authors.affiliation: Research and Development Teva Pharmaceuticals, Netanya, Israel Ofer.Spiegelstein@teva.co.il.
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: Van Gerven
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Pradeep J
authors.initials: PJ
authors.lastname: Nathan
authors.affiliation: Community Research Inc, Cincinnati, OH, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Maynard
authors.affiliation: Community Research Inc, Cincinnati, OH, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Mayleben
authors.affiliation: Research and Development Teva Pharmaceuticals, West Chester, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Hellriegel
authors.affiliation: Research and Development Teva Pharmaceuticals, West Chester, PA, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006632:Histamine / Q000378:metabolism*; D006633:Histamine Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D018697:Nootropic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000652:urine; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000652:urine; D011968:Receptors, Histamine / Q000378:metabolism*; D055815:Young Adult
chemical_list: D006633:Histamine Antagonists; D018697:Nootropic Agents; D011724:Pyridazines; D011759:Pyrrolidines; D011968:Receptors, Histamine; D006632:Histamine; C561238:6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one
keywords: Pharmacokinetics and drug metabolism; central nervous system (CNS); clinical trials (CTR); histamine-3 receptor antagonist; pharmacodynamics (PDY); population pharmacokinetics