A Double-Blind, Placebo- and Positive-Controlled, Randomized, Partial 6-way Crossover Study to Investigate the Pharmacodynamics and Pharmacokinetics of CEP-26401 (5, 25, and 125 μg) Following Single-Dose Administration to Healthy Subjects

This is a single center, double-blind, placebo and positive-controlled, randomized, partial 6-way cross-over study to investigate the pharmacodynamics and pharmacokinetics of CEP-26401 (5, 25, and 125 μg) following single-dose administration to healthy male and female subjects.

Start Date01 Aug 2013

Sponsor / Collaborator

Teva Branded Pharmaceutical Products R&D, Inc.

100 Clinical Results associated with Irdabisant

100 Translational Medicine associated with Irdabisant

100 Patents (Medical) associated with Irdabisant

Literatures (Medical) associated with Irdabisant

01 May 2019·British Journal of Clinical PharmacologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Hellriegel, Edward ; Fetell, Michael ; Gershon, Ari ; Zuiker, Rob ; Baakman, Anne C. ; Spiegelstein, Ofer ; Gross, Nicholas ; Gilgun‐Sherki, Yossi ; van Gerven, Joop M.A. ; Yang, Ronghua

AimsIn previous studies, the histamine‐3 receptor antagonist CEP‐26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose‐dependent disruption of sleep. In the current study, 3 low‐dose levels of CEP‐26401 were compared with modafinil and donepezil.MethodsIn this double‐blind, placebo‐ and positive‐controlled, randomized, partial 6‐way cross‐over study, 40 healthy subjects received single doses of placebo, CEP‐26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose.ResultsThe main endpoint between‐errors of the spatial working memory‐10‐boxes task only improved for the 125 μg dose of CEP‐26401 with a difference of 2.92 (confidence interval [CI] –1.21 to 7.05), 3.24 (CI –1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP‐26401, −1.65 (CI –0.572 to 1.96) for modafinil and − 3.55 (CI –7.13 to 0.03) for donepezil. CEP‐26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N‐back, but a dose‐related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP‐26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone.DiscussionOf the doses tested, the 25 μg dose of CEP‐26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP‐26401 can have beneficial effects in clinical practice remains to be studied.

01 Oct 2016·Journal of PsychopharmacologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Mayleben, David W ; Maynard, James P ; Spiegelstein, Ofer ; Van Gerven, Joop ; Yang, Ronghua ; Nathan, Pradeep J ; Hellriegel, Edward ; Stevens, Jasper

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.

01 Jun 2012·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists

Q4 · MEDICINE

Article

Author: Lyons, Jacquelyn ; Raddatz, Rita ; Aimone, Lisa D. ; Josef, Kurt A. ; Hudkins, Robert L.

A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.

100 Deals associated with Irdabisant

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Indication	Highest Phase	Country/Location	Organization	Date
Cognitive Dysfunction	Phase 1	NL	Teva Pharmaceutical Industries Ltd.	01 Aug 2013
Cognitive Dysfunction	Phase 1	NL	Teva Branded Pharmaceutical Products R&D, Inc.	01 Aug 2013
Cognition Disorders	Phase 1	US	Teva Pharmaceutical Industries Ltd.	-

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