title: Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies.
abstract: OBJECTIVE
  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 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.
  
  
  RESULTS
  In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Forum Pharmaceuticals, Boston, Massachusetts.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
authors.affiliation: PRA International, Zuidlaren, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Hilhorst
authors.affiliation: PRA International, Zuidlaren, The Netherlands.
authors.forename: André
authors.initials: A
authors.lastname: Van Vliet
authors.affiliation: Brown University, Providence, Rhode Island.
authors.forename: Peter
authors.initials: P
authors.lastname: Snyder
authors.affiliation: Forum Pharmaceuticals, Boston, Massachusetts.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Palfreyman
authors.affiliation: Forum Pharmaceuticals, Boston, Massachusetts.
authors.forename: Maria
authors.initials: M
authors.lastname: Gawryl
authors.affiliation: Forum Pharmaceuticals, Boston, Massachusetts.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dgetluck
authors.affiliation: Forum Pharmaceuticals, Boston, Massachusetts.
authors.forename: Monica
authors.initials: M
authors.lastname: Massaro
authors.affiliation: PRA International, Zuidlaren, The Netherlands.
authors.forename: Renger
authors.initials: R
authors.lastname: Tiessen
authors.affiliation: PRA International, Zuidlaren, The Netherlands.
authors.forename: Wia
authors.initials: W
authors.lastname: Timmerman
authors.affiliation: Forum Pharmaceuticals, Boston, Massachusetts. Electronic address: dhilt@forumpharma.com.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Hilt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D002214:Capsules; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic; D012737:Sex Factors; D013810:Therapeutic Equivalency; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C573817:7-chloro-N-quinuclidin-3-yl-benzo(b)thiophene-2-carboxamide; D002214:Capsules; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D013876:Thiophenes
keywords: bioavailability; encenicline cognition; pharmacodynamics; pharmacokinetic profile; α(7) nicotinic acetylcholine receptor agonist