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Disposition and metabolism of [14C]LCZ696, an angiotensin receptor neprilysin inhibitor, in healthy volunteers

Flarakos, Jimmy and Du, Yancy and Bedman, Timothy and Chandra, Priya and Al-Share, Qusai and Jordaan, Pierre and Wang, Lai and Gu, Helen and Mangold, James and Albrecht, Diego and Lin, Tsu-Han (2016) Disposition and metabolism of [14C]LCZ696, an angiotensin receptor neprilysin inhibitor, in healthy volunteers. Xenobiotica.

Abstract

1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor.
2. Following oral administration, [14C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5 – 1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ~1.3 h, ~12 h and ~21 h, respectively.
3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7 to 67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and in feces, total accounting for ~85.5% of the total dose.
4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions

Item Type: Article
Keywords: LCZ696, AHU377, LBQ657 and Sacubitril/ Valsartan (formerly LCZ696)
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/24150

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