Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition.
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.
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. a.danser@erasmusmc.nl.
Joanna
J
Balcarek
Bruno
B
Sevá Pessôa
Catherine
C
Bryson
Michel
M
Azizi
Joël
J
Ménard
Ingrid M
IM
Garrelds
Gerard
G
McGeehan
Richard A
RA
Reeves
Sue G
SG
Griffith
A H Jan
AH
Danser
Richard
R
Gregg
D000293:Adolescent; D000328:Adult; D000450:Aldosterone / Q000378:metabolism; D000577:Amides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005650:Fumarates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D055815:Young Adult; D000092502:Renin Inhibitors
D000450:Aldosterone; D000577:Amides; D000804:Angiotensin II; D002219:Carbamates; D005650:Fumarates; D010880:Piperidines; D012083:Renin; D000092502:Renin Inhibitors; C582069:methyl (2-((3-chlorophenyl)(1-((2-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propyl)carbamoyl)piperidin-3-yl)methoxy)ethyl)carbamate; C446481:aliskiren
aldosterone; angiotensins; blood pressure; humans; pharmacokinetics; renin