bolized. Valsartan is minimally metabolized; approximately 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified at low concentrations (< 10%) in plasma. LBQ657 crosses the blood brain barrier to a minimal extent (0.28%). The average volume of distribution of sacubitril and valsartan are 103 and 75 L, respectively. Following oral administration, 52—68% of sacubitril (primarily as metabolite) and approximately 13% of valsartan and its metabolites are excreted in urine. The remaining drug and metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan exhibit a mean elimination half-life (T1/2) of approximately 1.4, 11.5, and 9.9 hours, respectively.
In a 21-day study of patients with heart failure and reduced ejection fraction, sacubitril; valsartan administration resulted in significantly increased urine atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) and plasma cGMP, and decreased plasma N-terminal pro b-type natriuretic peptide (NT-proBNP), aldosterone, and endothelin-1. Sacubitril; valsartan blocked the AT1-receptor resulting in increased plasms renin activity and plasms renin concentrations.
Oral Route
Following oral administration, the peak plasma concentrations of sacubitril, its metabolite, and valsartan are reached in 0.5, 2, and 1.5 hours, respectively. Oral absolute bioavailability of sacubitril is estimated to be >/= 60%. Valsartan when combined in the sacubitril; valsartan combination product is more bioavailable than valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril; valsartan is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed formulations. Steady state concentrations of sacubitril, its metabolite, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate; however, the metabolite of sacubitril accumulates by 1.6-fold. Food has no clinically significant effect on the systemic exposure of sacubitril; valsartan. |
