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.