Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition

Hypertension. 2014 May;63(5):942-50. doi: 10.1161/HYPERTENSIONAHA.113.02893. Epub 2014 Jan 27.


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.

Keywords: aldosterone; angiotensins; blood pressure; humans; pharmacokinetics; renin.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aldosterone / metabolism
  • Amides / adverse effects
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Angiotensin II / metabolism
  • Blood Pressure / drug effects
  • Carbamates / adverse effects
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • Fumarates / adverse effects
  • Fumarates / pharmacokinetics
  • Fumarates / pharmacology
  • Hemodynamics / drug effects
  • Humans
  • Kidney / drug effects*
  • Kidney / metabolism
  • Male
  • Middle Aged
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology*
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Young Adult


  • Amides
  • Carbamates
  • Fumarates
  • Piperidines
  • methyl (2-((3-chlorophenyl)(1-((2-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propyl)carbamoyl)piperidin-3-yl)methoxy)ethyl)carbamate
  • Angiotensin II
  • Aldosterone
  • aliskiren
  • Renin