Disposition and metabolism of [14C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects

• Published in: Xenobiotica Vol. 46; no. 11; pp. 986 - 1000
• Main Authors: Flarakos, Jimmy, Du, Yancy, Bedman, Timothy, Al-Share, Qusai, Jordaan, Pierre, Chandra, Priya, Albrecht, Diego, Wang, Lai, Gu, Helen, Einolf, Heidi J., Huskey, Su-Er, Mangold, James B.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.11.2016
• Subjects: Adult; Aminobutyrates - metabolism; and LBQ657; Angiotensin II Type 1 Receptor Blockers - metabolism; Drug Combinations; Human ADME; Humans; LCZ696; Neprilysin - antagonists & inhibitors; sabubitril; sacubitril/valsartan; Tetrazoles - metabolism; valsartan; Valsartan - metabolism; sabubitril; valsartan; LCZ696; and LBQ657; Human ADME; sacubitril/valsartan
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2015.1014944

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, [ 14 C]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, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% 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 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 clinically was found to be low.