Multiple Ascending Dose Study With the New Renin Inhibitor VTP-27999: Nephrocentric Consequences of Too Much Renin Inhibition

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2014-05, Vol.63 (5), p.942-950
• Main Authors: BALCAREK, Joanna, PESSOA, Bruno Sevá, GREGG, Richard, BRYSON, Catherine, AZIZI, Michel, MENARD, Joël, GARRELDS, Ingrid M, MCGEEHAN, Gerard, REEVES, Richard A, GRIFFITH, Sue G, JAN DANSER, A. H
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aldosterone - metabolism; Amides - adverse effects; Amides - pharmacokinetics; Amides - pharmacology; Angiotensin II - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Carbamates - adverse effects; Carbamates - pharmacokinetics; Carbamates - pharmacology; Cardiology. Vascular system; Dose-Response Relationship, Drug; Female; Fumarates - adverse effects; Fumarates - pharmacokinetics; Fumarates - pharmacology; Hemodynamics - drug effects; Humans; Kidney - drug effects; Kidney - metabolism; Male; Medical sciences; Middle Aged; Piperidines - adverse effects; Piperidines - pharmacokinetics; Piperidines - pharmacology; Renin - antagonists & inhibitors; Renin - blood; Young Adult
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.113.02893

This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit.