title: Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor.
abstract: OBJECTIVE
  LCZ696 (sacubitril/valsartan), an angiotensin receptor 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 pharmacokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5.
  
  
  RESULTS
  The steady-state Cmax and AUC0-24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state Cmax of sacubitrilat was increased by ∼60 % in patients irrespective 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 AUC0-24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment.
  
  
  CONCLUSIONS
  Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. surya.ayalasomayajula@novartis.com.
authors.forename: Surya P
authors.initials: SP
authors.lastname: Ayalasomayajula
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Langenickel
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Jordaan
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Chandra
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Diego
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: Novartis Healthcare Pvt Ltd, Hyderabad, Telangana, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
mesh_terms: D000328:Adult; D000613:Aminobutyrates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds; D004338:Drug Combinations; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000502:physiology; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000378:metabolism* / Q000503:physiopathology; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Angiotensin receptor neprilysin inhibitor; LCZ696; Pharmacokinetics; Renal impairment; Sacubitril; Valsartan