학술논문
Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Encenicline, a Selective α7 Nicotinic Receptor Partial Agonist, in Single Ascending-dose and Bioavailability Studies.
Document Type
Article
Author
Source
Subject
*PHARMACOKINETICS
*ACADEMIC medical centers
*ALZHEIMER'S disease
*AMBULATORY electrocardiography
*ANALYSIS of variance
*BIOAVAILABILITY
*BLOOD testing
*CELL receptors
*COGNITION
*CONFIDENCE intervals
*CROSSOVER trials
*DOSE-response relationship in biochemistry
*DRUGS
*ELECTROCARDIOGRAPHY
*ELECTROENCEPHALOGRAPHY
*NEUROPSYCHOLOGICAL tests
*NICOTINE
*PHYSICAL diagnosis
*PLACEBOS
*QUESTIONNAIRES
*REGRESSION analysis
*RESEARCH funding
*SAFETY
*T-test (Statistics)
*RANDOMIZED controlled trials
*BLIND experiment
*DATA analysis software
*DESCRIPTIVE statistics
*PHARMACODYNAMICS
DRUG therapy for schizophrenia
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Language
ISSN
0149-2918
Abstract
Purpose: Encenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 singledose 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 Cmax (mean range 0.59-100 ng/mL) and AUC0-∞ (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. [ABSTRACT FROM AUTHOR]