Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective alpha7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies.

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Barbier AJ, Hilhorst M, Van Vliet A, Snyder P, Palfreyman MG, Gawryl M, Dgetluck N, Massaro M, Tiessen R, Timmerman W, Hilt DC

Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective alpha7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies.

Clin Ther. 2015 Feb 1;37(2):311-24. doi: 10.1016/j.clinthera.2014.09.013. Epub 2014 Oct 14.

PubMed ID

25438724 [ View in PubMed

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Abstract

PURPOSE: Encenicline (EVP-6124) is a selective alpha7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. METHODS: A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FINDINGS: In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (mean range 0.59-100 ng/mL) and AUC0-infinity (mean range 45.6-8890 ng.h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. IMPLICATIONS: Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Encenicline	Neuronal acetylcholine receptor subunit alpha-7	Protein	Humans	Yes	Partial agonist	Details