Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension

Clin Pharmacol Ther. 2018 Mar;103(3):468-476. doi: 10.1002/cpt.759. Epub 2017 Nov 3.

Abstract

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / adverse effects
  • Aminobutyrates / pharmacokinetics*
  • Aminobutyrates / pharmacology*
  • Angiotensin Receptor Antagonists / adverse effects
  • Angiotensin Receptor Antagonists / pharmacokinetics*
  • Angiotensin Receptor Antagonists / pharmacology*
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / pharmacokinetics*
  • Antihypertensive Agents / pharmacology*
  • Atrial Natriuretic Factor / urine
  • Blood Pressure / drug effects
  • Cyclic GMP / urine
  • Double-Blind Method
  • Drug Interactions
  • Humans
  • Hypertension / drug therapy*
  • Male
  • Middle Aged
  • Sildenafil Citrate / adverse effects
  • Sildenafil Citrate / pharmacokinetics*
  • Sildenafil Citrate / pharmacology*
  • Tetrazoles / adverse effects
  • Tetrazoles / pharmacokinetics*
  • Tetrazoles / pharmacology*

Substances

  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Tetrazoles
  • Atrial Natriuretic Factor
  • Sildenafil Citrate
  • Cyclic GMP
  • sacubitril-valsartan

Associated data

  • ClinicalTrials.gov/NCT01601470