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- Title
Entry-into-humans study with a new direct renin inhibitor.
- Authors
Nicolas, Laurent; Gutierrez, Marcelo; Binkert, Christoph; Dingemanse, Jasper
- Abstract
Purpose: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of escalating single oral doses of ACT-077825, a novel orally active renin inhibitor, in healthy male subjects. Methods: In this single-center, double-blind, placebo- and active-controlled (with enalapril) randomized study, 70 subjects received a single dose of ACT-077825 (1-1,000 mg), placebo, or enalapril 20 mg under fasted conditions. The main pharmacokinetic endpoints were area under the plasma ACT-077825 concentration-time curve from time zero to infinity and the terminal half-life (t). The pharmacodynamic endpoints included immunoactive active renin (iAR) plasma concentrations and plasma renin activity (PRA). Standard laboratory and safety data were collected. Results: Of the few adverse events reported, diarrhea and headache were the most frequent. The pharmacokinetics of ACT-077825 were dose-proportional in the dose range 100 to 1,000 mg. Terminal t, best characterized following a dose of 1,000 mg, was 41.6 h and t 4-5 h post-dose. ACT-077825 dose-dependently increased iAR and decreased PRA, effects that were associated with a decrease in blood pressure at 1,000 mg, similar to following treatment with enalapril. Conclusion: The results provide evidence that ACT-077825, with a pharmacokinetic profile consistent with a once-a-day dosing regimen, may represent an effective antihypertensive agent and pave the way toward a multiple-ascending dose study.
- Subjects
ALDOSTERONE; ANGIOTENSINS; CONFIDENCE intervals; CREATININE; ENZYME inhibitors; OLIGOPEPTIDES; POTASSIUM; RADIOIMMUNOASSAY; RENIN; RESEARCH funding; STATISTICAL sampling; SODIUM; RANDOMIZED controlled trials; BLIND experiment; DATA analysis software; DESCRIPTIVE statistics; ENALAPRIL; INVESTIGATIONAL drugs; PHARMACODYNAMICS
- Publication
European Journal of Clinical Pharmacology, 2012, Vol 68, Issue 9, p1257
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-012-1253-2