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Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor

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An Erratum to this article was published on 19 May 2017

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Abstract

Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5–2.0, and 2.0–3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration–time curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug–drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (~2.0-fold) and area under the plasma concentration–time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration–time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration–time curves, while the area under the plasma concentration–time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration–time curves of valsartan and sacubitrilat ~2.1-fold.

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Change history

  • 19 May 2017

    An erratum to this article has been published.

References

  1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.

    Article  PubMed  Google Scholar 

  2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810–52.

    Article  PubMed  Google Scholar 

  3. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651–8.

    Article  CAS  PubMed  Google Scholar 

  4. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001–7.

    Article  Google Scholar 

  5. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9–13.

    Article  Google Scholar 

  6. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure: randomized aldactone evaluation study investigators. N Engl J Med. 1999;341(10):709–17.

    Article  CAS  PubMed  Google Scholar 

  7. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  8. Braunwald E. ACE inhibitors: a cornerstone of the treatment of heart failure. N Engl J Med. 1991;325(5):351–3.

    Article  CAS  PubMed  Google Scholar 

  9. McMurray JJ. CONSENSUS to EMPHASIS: the overwhelming evidence which makes blockade of the renin-angiotensin-aldosterone system the cornerstone of therapy for systolic heart failure. Eur J Heart Fail. 2011;13(9):929–36.

    Article  CAS  PubMed  Google Scholar 

  10. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4–25.

    Article  PubMed  Google Scholar 

  11. Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol. 2014;176(3):630–9.

    Article  PubMed  Google Scholar 

  12. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol. 2007;50(25):2357–68.

    Article  CAS  PubMed  Google Scholar 

  13. Hawkridge AM, Heublein DM, Bergen HR 3rd, et al. Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proc Natl Acad Sci USA. 2005;102(48):17442–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Niederkofler EE, Kiernan UA, O’Rear J, et al. Detection of endogenous B-type natriuretic peptide at very low concentrations in patients with heart failure. Circ Heart Fail. 2008;1(4):258–64.

    Article  CAS  PubMed  Google Scholar 

  15. Mangiafico S, Costello-Boerrigter LC, Andersen IA, et al. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34(12):886–893c.

    Article  CAS  PubMed  Google Scholar 

  16. Langenickel TH, Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Today. 2012;9(4):e131–9.

    Google Scholar 

  17. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.

    Article  PubMed  Google Scholar 

  18. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  19. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68(13):1476–88.

    Article  PubMed  Google Scholar 

  20. Vazir A, Solomon SD. Management strategies for heart failure with preserved ejection fraction. Heart Fail Clin. 2014;10(4):591–8.

    Article  PubMed  Google Scholar 

  21. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50(4):401–14.

    Article  CAS  PubMed  Google Scholar 

  22. Flarakos J, Du Y, Bedman T, et al. Disposition and metabolism of [C] sacubitril/valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects. Xenobiotica. 2016;46(11):986–1000s.

    Article  CAS  PubMed  Google Scholar 

  23. Feng L, Karpinski PH, Sutton P, et al. LCZ696: a dual-acting sodium supramolecular complex. Tetrahedron Lett. 2012;53(3):275–6.

    Article  CAS  Google Scholar 

  24. Ayalasomayajula S, Langenickel T, Chandra P, et al. Effect of food on the oral bioavailability of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects. Int J Clin Pharmacol Ther. 2016;54(12):1012–8.

    Article  PubMed  Google Scholar 

  25. Ayalasomayajula S, Jordaan P, Pal P, et al. Assessment of drug interaction potential between LCZ696, an angiotensin receptor neprilysin inhibitor, and digoxin or warfarin. Clin Pharmacol Biopharm. 2015;4:147.

    Article  Google Scholar 

  26. Nadeem S, Asif H, Lakshita C, et al. Pharmacological and pharmaceutical profile of valsartan: a review. J Appl Pharm Sci. 2011;01(04):12–9.

    Google Scholar 

  27. Novartis. Entresto™ (sacubitril and valsartan): US prescribing information. 2015. Available from: http://www.pharma.us.novartis.com. Accessed 21 Nov 2015.

  28. Flesch G, Muller P, Lloyd P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol. 1997;52(2):115–20.

    Article  CAS  PubMed  Google Scholar 

  29. Ayalasomayajula S, Pan W, Han Y, et al. Assessment of drug-drug interaction potential between atorvastatin and LCZ696, a novel angiotensin receptor neprilysin inhibitor, in healthy Chinese male subjects. Eur J Drug Metab Pharmacokinet. 2017;42(2):309–18.

    Article  CAS  PubMed  Google Scholar 

  30. Akahori M, Ayalasomayajula S, Langenickel T, et al. Pharmacokinetics after single ascending dose, food effect, and safety of sacubitril/valsartan (LCZ696), an angiotensin receptor and neprilysin inhibitor, in healthy Japanese subjects. Eur J Drug Metab Pharmacokinet. 2016. [Epub ahead of print].

  31. US Food and Drug Administration. Diovan: prescribing information. 2014. Available from: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/diovan.pdf. Accessed 13 Apr 2017.

  32. Sunkara G, Jiang X, Reynolds C, et al. Effect of food on the oral bioavailability of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects. Clin Pharmacol Drug Dev. 2014;3(6):487–92.

    Article  CAS  PubMed  Google Scholar 

  33. Colussi DM, Parisot C, Rossolino ML, et al. Protein binding in plasma of valsartan, a new angiotensin II receptor antagonist. J Clin Pharmacol. 1997;37(3):214–21.

    Article  CAS  PubMed  Google Scholar 

  34. Langenickel TH, Tsubouchi C, Ayalasomayajula S, et al. The effect of LCZ696 (sacubitril/valsartan) on amyloid-beta concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol. 2016;81(5):878–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shi J, Wang X, Nguyen J, et al. Sacubitril is selectively activated by carboxylesterase 1 (CES1) in the liver and the activation is affected by CES1 genetic variation. Drug Metab Dispos. 2016;44(4):554–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nakashima A, Kawashita H, Masuda N, et al. Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes. Xenobiotica. 2005;35(6):589–602.

    Article  CAS  PubMed  Google Scholar 

  37. Waldmeier F, Flesch G, Muller P, et al. Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose. Xenobiotica. 1997;27(1):59–71.

    Article  CAS  PubMed  Google Scholar 

  38. Kobalava Z, Kotovskaya Y, Averkov O, et al. Pharmacodynamic and pharmacokinetic profiles of sacubitril/valsartan (LCZ696) in patients with heart failure and reduced ejection fraction. Cardiovasc Ther. 2016;34(4):191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Myers RP, Cerini R, Sayegh R, et al. Cardiac hepatopathy: clinical, hemodynamic, and histologic characteristics and correlations. Hepatology. 2003;37(2):393–400.

    Article  PubMed  Google Scholar 

  40. Moller S, Bernardi M. Interactions of the heart and the liver. Eur Heart J. 2013;34(36):2804–11.

    Article  PubMed  Google Scholar 

  41. Cleland JG, Carubelli V, Castiello T, et al. Renal dysfunction in acute and chronic heart failure: prevalence, incidence and prognosis. Heart Fail Rev. 2012;17(2):133–49.

    Article  CAS  PubMed  Google Scholar 

  42. Prasad PP, Yeh CM, Gurrieri P, et al. Pharmacokinetics of multiple doses of valsartan in patients with heart failure. J Cardiovasc Pharmacol. 2002;40(5):801–7.

    Article  CAS  PubMed  Google Scholar 

  43. Prasad P, Kalbag J, Hester A. Assessment of dose proportionality of an angiotensin II receptor blocker, valsartan, following single doses of 80, 160 and 320 mg to healthy subjects (abstract). Pharm Sci. 1998;S144.

  44. Ayalasomayajula SP, Langenickel TH, Jordaan P, et al. Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor. Eur J Clin Pharmacol. 2016;72:1065–73.

    Article  CAS  PubMed  Google Scholar 

  45. Kulmatycki K, Langenickel T, Ng D, et al. Pharmacokinetics of single-dose LCZ696 in subjects with mild and moderate hepatic impairment. Clin Pharmacol Drug Dev. 2014;3(Suppl. 1):21.

    Google Scholar 

  46. Writing Committee Members. ACC/AHA Task Force members. ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Failure Society of America. J Card Fail. 2016;22(9):659–69.

    Article  Google Scholar 

  47. Ayalasomayajula S, Langenikel T, Malcolm K, et al. In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696). J Clin Pharm Ther. 2016;41:424–31.

    Article  CAS  PubMed  Google Scholar 

  48. Hsiao HL, Langenickel TH, Greeley M, et al. Pharmacokinetic drug–drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol. Clin Pharmacol Drug Dev. 2015;4(6):407–17.

    Article  CAS  PubMed  Google Scholar 

  49. Gan L, Jiang X, Mendonza A, et al. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects. Clin Pharmacol Drug Develop. 2015;5:27–39.

    Article  Google Scholar 

  50. Tenero D, Boike S, Boyle D, et al. Steady-state pharmacokinetics of carvedilol and its enantiomers in patients with congestive heart failure. J Clin Pharmacol. 2000;40(8):844–53.

    Article  CAS  PubMed  Google Scholar 

  51. Oldham HG, Clarke SE. In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(−)-carvedilol. Drug Metab Dispos. 1997;25(8):970–7.

    CAS  PubMed  Google Scholar 

  52. Bachmakov I, Werner U, Endress B, et al. Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol. 2006;20(3):273–82.

    Article  CAS  PubMed  Google Scholar 

  53. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194–9.

    Article  PubMed  Google Scholar 

  54. Budzynski J, Pulkowski G, Suppan K, et al. Improvement in health-related quality of life after therapy with omeprazole in patients with coronary artery disease and recurrent angina-like chest pain: a double-blind, placebo-controlled trial of the SF-36 survey. Health Qual Life Outcomes. 2011;9:77.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Ogawa R, Echizen H. Drug-drug interaction profiles of proton pump inhibitors. Clin Pharmacokinet. 2010;49(8):509–33.

    Article  CAS  PubMed  Google Scholar 

  56. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol. 2008;64(10):935–51.

    Article  CAS  PubMed  Google Scholar 

  57. Saydam M, Takka S. Bioavailability file: valsartan. FABAD J Pharm Sci. 2007;32:185–96.

    Google Scholar 

  58. Hirsh J. Oral anticoagulant drugs. N Engl J Med. 1991;324(26):1865–75.

    Article  CAS  PubMed  Google Scholar 

  59. Black DJ, Kunze KL, Wienkers LC, et al. Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos. 1996;24(4):422–8.

    CAS  PubMed  Google Scholar 

  60. Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med. 2003;3(3):221–30.

    Article  PubMed  Google Scholar 

  61. Serlin MJ, Breckenridge AM. Drug interactions with warfarin. Drugs. 1983;25(6):610–20.

    Article  CAS  PubMed  Google Scholar 

  62. National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III): final report. Circulation. 2002;106(25):3143–421.

    Google Scholar 

  63. European Association for Cardiovascular Prevention and Rehabilitation, Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769–818.

    Article  Google Scholar 

  64. McMurray JJ, Packer M, Desai AS, et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Niemi M. Role of OATP transporters in the disposition of drugs. Pharmacogenomics. 2007;8(7):787–802.

    Article  CAS  PubMed  Google Scholar 

  67. Kindla J, Fromm MF, Konig J. In vitro evidence for the role of OATP and OCT uptake transporters in drug-drug interactions. Expert Opin Drug Metab Toxicol. 2009;5(5):489–500.

    Article  CAS  PubMed  Google Scholar 

  68. Higgins JW, Bao JQ, Ke AB, et al. Utility of Oatp1a/1b-knockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein. Drug Metab Dispos. 2014;42(1):182–92.

    Article  CAS  PubMed  Google Scholar 

  69. Kunze A, Huwyler J, Camenisch G, et al. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos. 2014;42(9):1514–21.

    Article  PubMed  Google Scholar 

  70. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565–81.

    Article  CAS  PubMed  Google Scholar 

  71. Vallon V, Rieg T, Ahn SY, et al. Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008;294(4):F867–73.

    Article  CAS  PubMed  Google Scholar 

  72. Yamashiro W, Maeda K, Hirouchi M, et al. Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006;34(7):1247–54.

    Article  CAS  PubMed  Google Scholar 

  73. Ponto LL, Schoenwald RD. Furosemide (frusemide): a pharmacokinetic/pharmacodynamic review (Part I). Clin Pharmacokinet. 1990;18(5):381–408.

    Article  CAS  PubMed  Google Scholar 

  74. Bindschedler M, Degen P, Flesch G, et al. Pharmacokinetic and pharmacodynamic interaction of single oral doses of valsartan and furosemide. Eur J Clin Pharmacol. 1997;52(5):371–8.

    Article  CAS  PubMed  Google Scholar 

  75. Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis. 2002;44(4):251–66.

    Article  CAS  PubMed  Google Scholar 

  76. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006;113(21):2556–64.

    Article  PubMed  Google Scholar 

  77. de Lannoy IA, Silverman M. The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin. Biochem Biophys Res Commun. 1992;189(1):551–7.

    Article  PubMed  Google Scholar 

  78. Hori R, Okamura N, Aiba T, et al. Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther. 1993;266(3):1620–5.

    CAS  PubMed  Google Scholar 

  79. Wessler JD, Grip LT, Mendell J, et al. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495–502.

    Article  CAS  PubMed  Google Scholar 

  80. Hill NS, Antman EM, Green LH, et al. Intravenous nitroglycerin: a review of pharmacology, indications, therapeutic effects and complications. Chest. 1981;79(1):69–76.

    Article  CAS  PubMed  Google Scholar 

  81. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol. 2002;53(Suppl. 1):5S–12S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281–357.

    Article  CAS  PubMed  Google Scholar 

  83. Niemeyer C, Hasenfuss G, Wais U, et al. Pharmacokinetics of hydrochlorothiazide in relation to renal function. Eur J Clin Pharmacol. 1983;24(5):661–5.

    Article  CAS  PubMed  Google Scholar 

  84. Beermann B, Groschinsky-Grind M, Rosen A. Absorption, metabolism, and excretion of hydrochlorothiazide. Clin Pharmacol Ther. 1976;19(5 Pt 1):531–7.

    Article  CAS  PubMed  Google Scholar 

  85. Chung N, Baek S, Chen MF, et al. Expert recommendations on the challenges of hypertension in Asia. Int J Clin Pract. 2008;62(9):1306–12.

    Article  CAS  PubMed  Google Scholar 

  86. Wang JG, Kario K, Lau T, et al. Use of dihydropyridine calcium channel blockers in the management of hypertension in Eastern Asians: a scientific statement from the Asian Pacific Heart Association. Hypertens Res. 2011;34(4):423–30.

    Article  CAS  PubMed  Google Scholar 

  87. Wang JG, Li Y. Characteristics of hypertension in Chinese and their relevance for the choice of antihypertensive drugs. Diabetes Metab Res. 2012;28:67–72.

    Article  Google Scholar 

  88. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2009). Hypertens Res. 2009;32(1):3–107.

    CAS  PubMed  Google Scholar 

  89. Zhu Y, Wang F, Li Q, et al. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014;42(2):245–9.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang H, Cui D, Wang B, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet. 2007;46(2):133–57.

    Article  CAS  PubMed  Google Scholar 

  91. Moreno I, Quinones L, Catalan J, et al. Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study [in Spanish]. Biomedica. 2012;32(4):570–7.

    Article  PubMed  Google Scholar 

  92. Rakugi H, Kario K, Yamaguchi M, et al. Efficacy and safety of LCZ696 compared with olmesartan in Japanese patients with systolic hypertension. Hypertens. 2014;64:A474.

    Google Scholar 

  93. Ito S, Satoh M, Tamaki Y, et al. Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Hypertens Res. 2015;38(4):269–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gan L, Langenickel T, Petruck J, et al. Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor. J Clin Pharmacol. 2016;56(1):78–86.

    Article  CAS  PubMed  Google Scholar 

  95. Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J. 2015;36(38):2576–84.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Marsh S, Xiao M, Yu J, et al. Pharmacogenomic assessment of carboxylesterases 1 and 2. Genomics. 2004;84(4):661–8.

    Article  CAS  PubMed  Google Scholar 

  97. Suzaki Y, Uemura N, Takada M, et al. The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans. Eur J Clin Pharmacol. 2013;69(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  98. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70.

    Article  CAS  PubMed  Google Scholar 

  99. Brookman LJ, Rolan PE, Benjamin IS, et al. Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther. 1997;62(3):272–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge Iain O’Neill (contracted to Global Medical and Clinical Services, Novartis Ireland Ltd.) for providing editorial support.

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Authors and Affiliations

  1. Clinical Pharmacology, Allergan PLC, Suite 1900, Harborside V, 185 Hudson Street, Jersey, NJ, 07311, USA

    Surya Ayalasomayajula & Gangadhar Sunkara

  2. Novartis Institutes for Biomedical Research, Translational Medicine, Novartis Pharma AG, Basel, Switzerland

    Thomas Langenickel

  3. Novartis Healthcare Pvt. Ltd., Hyderabad, India

    Parasar Pal & Sreedevi Boggarapu

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  1. Surya Ayalasomayajula
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Correspondence to Surya Ayalasomayajula.

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All authors are employees of Novartis except Surya Ayalasomayajula, who was an employee of Novartis during the development of the manuscript.

Funding

All clinical pharmacokinetic studies are sponsored by Novartis Pharmaceuticals Co.

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An erratum to this article is available at https://doi.org/10.1007/s40262-017-0558-9.

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Ayalasomayajula, S., Langenickel, T., Pal, P. et al. Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor. Clin Pharmacokinet 56, 1461–1478 (2017). https://doi.org/10.1007/s40262-017-0543-3

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  • DOI: https://doi.org/10.1007/s40262-017-0543-3

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