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Pharmacokinetics, pharmacodynamics, and tolerability of ACT-077825, a new direct renin inhibitor after multiple-ascending doses in healthy subjects.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 2013 Jan; Vol. 61 (1), pp. 42-50. - Publication Year :
- 2013
-
Abstract
- This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCĪ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.
- Subjects :
- Adolescent
Adult
Angiotensin-Converting Enzyme Inhibitors administration & dosage
Antihypertensive Agents adverse effects
Area Under Curve
Biomarkers blood
Biomarkers urine
Blood Pressure drug effects
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Enalapril administration & dosage
Half-Life
Humans
Male
Metabolic Clearance Rate
Middle Aged
Models, Biological
Renin blood
Switzerland
Toluene administration & dosage
Toluene adverse effects
Toluene pharmacokinetics
Young Adult
Antihypertensive Agents administration & dosage
Antihypertensive Agents pharmacokinetics
Renin antagonists & inhibitors
Renin-Angiotensin System drug effects
Toluene analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4023
- Volume :
- 61
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23052033
- Full Text :
- https://doi.org/10.1097/FJC.0b013e318276d444