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.
['Balcarek|Joanna|J|', 'Sevá Pessôa|Bruno|B|', 'Bryson|Catherine|C|', 'Azizi|Michel|M|', 'Ménard|Joël|J|', 'Garrelds|Ingrid M|IM|', 'McGeehan|Gerard|G|', 'Reeves|Richard A|RA|', 'Griffith|Sue G|SG|', 'Danser|A H Jan|AH|', 'Gregg|Richard|R|']
D000293:Adolescent D000328:Adult D000450:Aldosterone D000577:Amides D000804:Angiotensin II D001794:Blood Pressure D002219:Carbamates D004305:Dose-Response Relationship, Drug D005260:Female D005650:Fumarates D006439:Hemodynamics D006801:Humans D007668:Kidney D008297:Male D008875:Middle Aged D010880:Piperidines D012083:Renin D055815:Young Adult
renin pharmacokinetics angiotensins aldosterone blood pressure humans