Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study

The aim of this study was to characterize the pharmacodynamics and the phar macokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers . This was a double-blind, randomized, placebo-controlled, single and multipl e dose study in elderly healthy male and female volunteers (n = 36). Four d oses 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 assess ed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantit ative electroencephalogram (EEG) and psychometric tests. S 17092 concentrat ions in plasma were quantified by high performance liquid chromatography wi th tandem mass spectrometric detection. PEP activity in plasma was dose-dependently inhibited both after administra tion 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 last ed at least 12 h after dose administration. S 17092 appeared to be a centra lly active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase i n alpha band following single administration at 4 h and 8 h postdosing. Whe n administered repeatedly over 7 days S 17092 did not appear to induce sign ificant lasting central nervous system (CNS) effects. In psychometric tests , response times in the numeric working memory were significantly reduced c ompared 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 wo rd recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (C-max) and area under the curve (A UC) 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 o n day 14. A high interindividual variability was observed at all dose level s. S 17092 was well tolerated with no clinically significant changes in lab oratory or physical parameters observed at any dose. S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, in creased alpha band EEG at the 100 mg dose and improved performance in two v erbal memory tests at the 1200 mg dose while there were disruption to the v igilance task. The results obtained in elderly healthy subjects indicated t hat S 17092 is suitable for once-daily dosing without any serious adverse e vents.