title: Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects .
abstract: OBJECTIVE
  Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes.
  
  
  METHODS
  This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal.
  
  
  RESULTS
  Following administration of LCZ696 after low- and high-fat meals, the mean Cmaxof sacubitril and sacubitrilat (the active neprilysin inhibitor) decreased by 42 - 54% and 19 - 28%, respectively, while the tmaxvalues increased. However, systemic exposure (AUCinfand AUClast) of sacubitril was slightly decreased (by 16% with low-fat meal) and that of sacubitrilat was unchanged in the presence of food. For valsartan, the Cmaxdecreased by ~ 40% when LCZ696 was administered after low- and high-fat meals. The systemic exposure of valsartan decreased by ~ 33% with a low-fat meal; however, it was unchanged with a high-fat meal. LCZ696 was generally safe and well tolerated in healthy subjects when administered under fasting or fed condition.
  
  
  CONCLUSIONS
  Overall, administration of LCZ696 with meals decreased the rate and extent of absorption of sacubitril with little impact on the systemic exposure to sacubitrilat, its active metabolite. The systemic exposure to valsartan was decreased in the presence of food. .
authors.forename: Surya
authors.initials: S
authors.lastname: Ayalasomayajula
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Langenickel
authors.forename: Priya
authors.initials: P
authors.lastname: Chandra
authors.forename: Edward D
authors.initials: ED
authors.lastname: Wolfson
authors.forename: Diego
authors.initials: D
authors.lastname: Albrecht
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
mesh_terms: D000293:Adolescent; D000328:Adult; D000613:Aminobutyrates / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists / Q000493:pharmacokinetics*; D001682:Biological Availability; D001713:Biphenyl Compounds; D018592:Cross-Over Studies; D004338:Drug Combinations; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000493:pharmacokinetics*; D000068756:Valsartan / Q000493:pharmacokinetics*
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination