title: Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization.
abstract: OBJECTIVE
  Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization.
  
  
  METHODS
  This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety.
  
  
  RESULTS
  Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups.
  
  
  CONCLUSIONS
  Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, CH-4002, Switzerland. thomas.langenickel@novartis.com.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Langenickel
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, CH-4002, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Jordaan
authors.affiliation: Translational Medicine, Clinical Sciences and Innovation, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Jesika
authors.initials: J
authors.lastname: Petruck
authors.affiliation: Integrated Quantitative Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Kode
authors.affiliation: Integrated Quantitative Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Soniya
authors.initials: S
authors.lastname: Vaidya
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Chandra
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, CH-4002, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
mesh_terms: D000293:Adolescent; D000328:Adult; D000613:Aminobutyrates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000068756:Valsartan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; C000609743:LBQ657; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Angiotensin receptor neprilysin inhibitor; Cardiac repolarization; Heart failure; LCZ696; QT prolongation; Sacubitril/valsartan