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

Abstract

Aims: 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.

Figure 1

The chemical structure of S 17092.

Figure 2

Mean values on PEP activity after single dose administration on day 1 and repeated dose administration on days 8–14 in elderly healthy volunteers. At day 1 the minimum PEP activity values (in nmol ml⁻¹ min⁻¹) were: 4.9 ± 1.1, 3.3 ± 0.9, 3.3 ± 0.6, 2.8 ± 0.6 for placebo (•), 100 mg (□), 400 mg (▵) and 800 mg (○) dose group, respectively. The PEP activity values at 12 h were (in nml ml⁻¹ min⁻¹) were: 5.7 ± 1.1, 4.5 ± 1.6, 3.8 ± 0.5, 3.1 ± 0.9 for placebo, 100 mg, 400 mg and 800 mg dose group, respectively.At day 14 the minimum PEP activity values (in nmol ml⁻¹ min⁻¹) were: 4.5 ± 1.2, 3.5 ± 0.8, 3.5 ± 0.4, 2.8 ± 0.8 for placebo, 100 mg, 400 mg and 800 mg dose group, respectively. The PEP activity values at 12 h (in nmol ml⁻¹ min⁻¹) were: 4.9 ± 1.2, 4.3 ± 1.1, 4.0 ± 0.4, 3.3 ± 0.8 for placebo, 100 mg, 400 mg and 800 mg dose group, respectively.

Figure 5

PEP activity (%) vs S 17092 plasma concentration, ♦ observed individual data. Thick line: tendency curve of the observed individual data, described by a polynominal relationship of the sixth degree. Thin line: population model described by the inhibitory Emax equation. Insert in right upper corner: % Emax vs S 17092 plasma concentration.

Figure 3

E; EG absolute power. Single dose effects on day 1. a) 4 h post dosing - pre-dosing, b) 8 h post dosing - pre dosing. placebo; 100 mg, 400 mg; 800 mg; 1200 mg S 17092.o

Figure 4

E; EG absolute power. Single dose effects on day 14. a) 4 h post dosing - pre-dosing, b) 8 h post dosing - pre dosing. placebo; 100 mg, 400 mg; 800 mg; 1200 mg S 17092.