PHARMACOKINETICS AND DISPOSITION Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor Surya P. Ayalasomayajula 1 & Thomas H. Langenickel 2 & Pierre Jordaan 2 & Wei Zhou 1 & Priyamvada Chandra 1 & Diego Albrecht 2 & Parasar Pal 3 & Iris Rajman 2 & Gangadhar Sunkara 1 Received: 30 March 2016 /Accepted: 18 May 2016 # Springer-Verlag Berlin Heidelberg 2016 Abstract Purpose LCZ696 (sacubitril/valsartan), an angiotensin recep- tor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and sacubitril (a prodrug), and its metabolite sacubitrilat (the active neprilysin inhibitor, formerly named as LBQ657), which is eliminated primarily via renal route. Since renal dysfunction is a common comorbidity in patients with HF, two open-label studies assessing the effect of mild, moderate, and severe renal impairment were conducted. Methods Patients with mild (N = 8; creatinine clearance [CrCl] 50 to ≤80 mL/min), moderate (N = 8; CrCl 30 to <50 mL/min), and severe (N = 6; CrCl <30 mL/min) renal impairment and matching healthy subjects (CrCl >80 mL/ min) for each severity group were enrolled to assess the phar- macokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5. Results The steady-state C max and AUC 0–24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state C max of sacubitrilat was increased by ∼60 % in patients irre- spective of degree of renal impairment; half-life increased from 12 h (in healthy subjects) to 21.1, 23.7, and 38.5 h, respectively; and AUC 0–24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment. Conclusion Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan expo- sure. LCZ696 was generally well tolerated in patients with renal impairment. Keywords Angiotensin receptor neprilysin inhibitor . LCZ696 . Pharmacokinetics . Renal impairment . Valsartan . Sacubitril Introduction Sacubitril/valsartan (LCZ696) is a novel orally active angio- tensin receptor neprilysin inhibitor (ARNI). It is approved to reduce the risk of cardiovascular (CV) death and hospitaliza- tion for heart failure (HF) in patients with chronic HF (New York Heart Association [NYHA] Functional Class II–IV) and reduced ejection fraction (HFrEF). LCZ696 is a sodium salt complex of sacubitril and valsartan in a 1:1 molar ratio. Following oral administration, LCZ696 provides systemic ex- posure to valsartan, an AT1-receptor blocker, and sacubitril (a prodrug formerly referred to as AHU377) [1]. Sacubitril is an inactive prodrug and is rapidly hydrolyzed by carboxyl ester- ases (CES) to form sacubitrilat (also reported as LBQ657), the active neprilysin inhibitor. It was reported that CES-1 but not CES-2 is involved in this conversion, while the role of other CES polymorphs is unknown [2]. Simultaneous inhibition of neprilysin and angiotensin II type-1 (AT1) receptor with LCZ696 showed superior benefits over enalapril in reducing the CV deaths and HF hospitalizations (primary composite endpoint) in the PARADIGM-HF trial in patients with HFrEF [3]. * Surya P. Ayalasomayajula surya.ayalasomayajula@novartis.com 1 Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA 2 Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, Switzerland 3 Novartis Healthcare Pvt Ltd, Hyderabad, Telangana, India Eur J Clin Pharmacol DOI 10.1007/s00228-016-2072-7