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 (t1/2). 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 t1/2, best characterized following a dose of 1,000 mg, was 41.6 h and tmax 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.
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Acknowledgements
This study was funded by Actelion Pharmaceuticals Ltd. The authors acknowledge the contributions of all subjects, investigators, and study personnel, including staff from the bioanalytical laboratory, involved in this trial.
Conflict of interest
Laurent B. Nicolas, Marcelo M. Gutierrez, Christoph Binkert, and Jasper Dingemanse are full-time employees of Actelion Pharmaceuticals Ltd. This study was sponsored by Actelion Pharmaceuticals Ltd.
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Nicolas, L.B., Gutierrez, M.M., Binkert, C. et al. Entry-into-humans study with a new direct renin inhibitor. Eur J Clin Pharmacol 68, 1257–1266 (2012). https://doi.org/10.1007/s00228-012-1253-2
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DOI: https://doi.org/10.1007/s00228-012-1253-2