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  • Title: Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/valsartan (LCZ696) in healthy subjects.
    Author: Schuehly U, Ayalasomayajula S, Buchbjerg J, Pal P, Golor G, Prescott MF, Sunkara G, Hinder M, Langenickel TH.
    Journal: Eur J Clin Pharmacol; 2018 Sep; 74(9):1121-1130. PubMed ID: 29974143.
    Abstract:
    PURPOSE: Sacubitril/valsartan (LCZ696) and nitroglycerin share the second messenger cGMP and lower blood pressure. Given the potential for co-administration of both drugs in patients with heart failure, this study was designed to investigate the potential for a pharmacodynamic drug interaction affecting blood pressure. METHODS: In this double-blind, placebo-controlled, randomised, crossover study, 40 healthy subjects received sacubitril/valsartan 200 mg bid (97/103 mg bid) or placebo for 5 days. Two hours after the morning dose of sacubitril/valsartan or placebo on day 5, subjects received intravenous nitroglycerin infusion at increasing doses up to 40 μg/min or placebo. Serial measurements of blood pressure (BP), heart rate, biomarkers and sacubitril/valsartan pharmacokinetics were conducted. RESULTS: Administration of nitroglycerin alone led to a dose- and time-dependent decrease in supine systolic BP (SBP) and diastolic BP (DBP) which was similar when nitroglycerin was co-administered with sacubitril/valsartan. At the highest dose of nitroglycerin, the mean (95% CI) decrease from baseline of SBP/DBP was 19.54 (- 21.99, - 17.09)/12.38 (- 13.85, - 10.92) mmHg for nitroglycerin alone compared to 22.63 (- 25.06, - 20.21)/12.94 (- 14.38, - 11.49) mmHg when co-administered with sacubitril/valsartan. Co-administration of sacubitril/valsartan and nitroglycerin did not result in further plasma cGMP increase compared to sacubitril/valsartan alone. The co-administration of nitroglycerin and sacubitril/valsartan was safe and well tolerated and did not impact the pharmacokinetics of sacubitril/valsartan. CONCLUSIONS: The results from this study demonstrate no pharmacodynamic drug interaction between nitroglycerin and sacubitril/valsartan in healthy subjects, suggesting that no change of dose selection and escalation recommendations or clinical monitoring during nitroglycerin administration is required.
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