title: Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study.
abstract: OBJECTIVE
  The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers.
  
  
  METHODS
  This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection.
  
  
  RESULTS
  PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5-2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t(1/2)) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose.
  
  
  CONCLUSIONS
  S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events.
authors.affiliation: Institut de Recherches Internationales Servier, 6 place des Pléiades, 92415 Courbevoie, France. morain@netgrs.com
authors.forename: P
authors.initials: P
authors.lastname: Morain
authors.forename: J L
authors.initials: JL
authors.lastname: Robin
authors.forename: G
authors.initials: G
authors.lastname: De Nanteuil
authors.forename: R
authors.initials: R
authors.lastname: Jochemsen
authors.forename: V
authors.initials: V
authors.lastname: Heidet
authors.forename: D
authors.initials: D
authors.lastname: Guez
mesh_terms: D000284:Administration, Oral; D000368:Aged; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D011594:Psychometrics / Q000379:methods; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D053778:Thiazolidines
chemical_list: D007211:Indoles; D011480:Protease Inhibitors; C118986:S 17092-1; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases