Dose-effect relationship of perindopril 10, 14 and 20mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers

• Published in: International journal of cardiology Vol. 222; pp. 648 - 653
• Main Authors: Monge, Matthieu, Paquet, Valérie, Bergerot, Damien, Zhygalina, Valentina, Blanchard, Anne
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2016
• Subjects: ACE inhibition; AcSDKP; Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Humans; Hyponatremia - blood; Hyponatremia - urine; Male; Oligopeptides - blood; Oligopeptides - urine; Perindopril - pharmacology; Perindopril arginine; Pharmacodynamics; Phase 1 study; Sodium, Dietary - administration & dosage; Sodium, Dietary - antagonists & inhibitors; Young Adult; Pharmacodynamics; Phase 1 study; Perindopril arginine; AcSDKP; ACE inhibition
• ISSN: 0167-5273; 1874-1754; 1874-1754
• DOI: 10.1016/j.ijcard.2016.07.164

We describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure. This randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48h for AcSDKP, ACE activity, and plasma active renin measurements. There were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48h of AcSDKP, 49.1 [95% CI: 15.3–82.0] nmol for 14 versus 10mg, and 73.2 [95% CI: 44.9–106.3] nmol for 20 versus 14mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects. Administration of perindopril arginine 10, 14, or 20mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.