Pharmacodynamic Modeling

Sacubitril/valsartan (LCZ696) Significantly Reduces Aldosterone and Increases cGMP Circulating Levels in a Canine Model of RAAS Activation


Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675mg/day) vs. placebo, sacubitril (360mg/day), valsartan (900mg/day), and benazepril (5mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n=18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on Day 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on Day 5. Compared with placebo, sacubitril/valsartan (675mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675mg administration was similar to that observed with valsartan 900mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.

Keywords: Angiotensin receptor neprilysin inhibitor, cGMP, plasma renin activity, sacubitril/valsartan, renin angiotensin aldosterone inhibitor