Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization

  • Eur J Clin Pharmacol. 2016 Aug;72(8):917-24. doi: 10.1007/s00228-016-2062-9.
Thomas H Langenickel  1 ,  Pierre Jordaan  2 ,  Jesika Petruck  3 ,  Kiran Kode  4 ,  Parasar Pal  4 ,  Soniya Vaidya  5 ,  Priya Chandra  6 ,  Iris Rajman  2
Affiliations
  • 1. Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, CH-4002, Switzerland. [email protected].
  • 2. Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, CH-4002, Switzerland.
  • 3. Translational Medicine, Clinical Sciences and Innovation, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 4. Integrated Quantitative Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
  • 5. Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 6. Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
PMID: 27083930 DOI: 10.1007/s00228-016-2062-9
Abstract

Purpose: 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.

Method: 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.

Conclusion: Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.

Keywords
Angiotensin receptor neprilysin inhibitor; Cardiac repolarization; Heart failure; LCZ696; QT prolongation; Sacubitril/valsartan.
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