Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction

Zhanna Kobalava, Yulia Kotovskaya, Oleg Averkov, Elena Pavlikova, Valentine Moiseev, Diego Albrecht, Priya Chandra, Surya Ayalasomayajula, Margaret F Prescott, Parasar Pal, Thomas H Langenickel, Pierre Jordaan, Iris Rajman, Zhanna Kobalava, Yulia Kotovskaya, Oleg Averkov, Elena Pavlikova, Valentine Moiseev, Diego Albrecht, Priya Chandra, Surya Ayalasomayajula, Margaret F Prescott, Parasar Pal, Thomas H Langenickel, Pierre Jordaan, Iris Rajman

Abstract

Aims: Concomitant renin-angiotensin-aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF.

Methods: This was an open-label, noncontrolled single-sequence study. After a 24-h run-in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II-IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]).

Results: On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio-to-baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT-proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin-1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100- and 200-mg doses, the Cmax and AUC0-12 h for sacubitril and LBQ657 were approximately dose-proportional while that of valsartan was less than dose-proportional.

Conclusions: Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

Keywords: Heart failure; LCZ696; Pharmacodynamics; Pharmacokinetics; Sacubitril/valsartan.

© 2016 John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Study design. *No patients participated in the titration period 1. ABPM, ambulatory blood pressure monitoring; ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; bid, twice daily; HF, heart failure; PD, pharmacodynamics; PK, pharmacokinetics.
Figure 2
Figure 2
Mean (±SD) levels of (A) plasma aldosterone, (B) plasma endothelin‐1 and (C and D) plasma and urine NT‐proBNP for patients receiving LCZ696 treatment. Data are presented as geometric mean and 95% confidence intervals; *P < 0.05. NT‐proBNP, N‐terminal pro‐hormone B‐type natriuretic peptide; SD, standard deviation.
Figure 3
Figure 3
Mean (SD) plasma concentration–time profiles of (A) sacubitril, (B) LBQ657, and (C) valsartan at steady state following administration of LCZ696 100 and 200 mg bid. bid, twice daily; SD, standard deviation.

References

    1. 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;50:401–414.
    1. Wang BH, Von Lueder TG, Kompa AR, et al. Combined angiotensin receptor blockade and neprilysin inhibition attenuates angiotensin‐II mediated renal cellular collagen synthesis. Int J Cardiol 2015;186:104–105.
    1. von Lueder TG, Wang BH, Kompa AR, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail 2015;8:71–78.
    1. Mangiafico S, Costello‐Boerrigter LC, Andersen IA, Cataliotti A, Burnett JC Jr. Neutral endopeptidase inhibition and the natriuretic peptide system: An evolving strategy in cardiovascular therapeutics. Eur Heart J 2013;34:886–893c.
    1. Potter LR, Abbey‐Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate‐dependent signaling functions. Endocr Rev 2006;27:47–72.
    1. Mehta PK, Griendling KK. Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007;292:C82–C97.
    1. Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood‐pressure reduction with LCZ696, a novel dual‐acting inhibitor of the angiotensin II receptor and neprilysin: A randomised, double‐blind, placebo‐controlled, active comparator study. Lancet 2010;375:1255–1266.
    1. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.
    1. Entresto Prescribing Information . US Food and Drug Administration Web Site [Internet]. 2015. Available from: .
    1. Entresto Summary of Product Characteristics . EMA Web Site [Internet]. 2015. Available from: .
    1. Liao WC, Vesterqvist O, Delaney C, et al. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects. Br J Clin Pharmacol 2003;56:395–406.
    1. Azizi M, Menard J, Bissery A, Guyene TT, Bura‐Riviere A. Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium‐replete normotensive individuals. Clin J Am Soc Nephrol 2007;2:947–955.
    1. Kenny AJ, Bourne A, Ingram J. Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C‐type natriuretic peptide and some C‐receptor ligands by endopeptidase‐24.11. Biochem J 1993;291(Pt 1):83–88.
    1. Martinez‐Rumayor A, Richards AM, Burnett JC, Januzzi JL Jr. Biology of the natriuretic peptides. Am J Cardiol 2008;101:3–8.
    1. Cioffi G, Tarantini L, Stefenelli C, et al. Changes in plasma N‐terminal proBNP levels and ventricular filling pressures during intensive unloading therapy in elderly with decompensated congestive heart failure and preserved left ventricular systolic function. J Card Fail 2006;12:608–615.
    1. Abassi Z, Golomb E, Keiser HR. Neutral endopeptidase inhibition increases the urinary excretion and plasma levels of endothelin. Metabolism 1992;41:683–685.
    1. Erdos EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J 1989;3:145–151.
    1. 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;341:709–717.
    1. Miura S, Suematsu Y, Matsuo Y, et al. Angiotensin II Receptor‐Neprilysin Inhibitor, LCZ696 Blocked Aldosterone Synthesis in Human Adrenocortical Cell Line. Eur Heart J 2015;36(Suppl 1):662.
    1. 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. doi:.
    1. Prasad PP, Yeh CM, Gurrieri P, Glazer R, McLeod J. Pharmacokinetics of multiple doses of valsartan in patients with heart failure. J Cardiovasc Pharmacol 2002;40:801–807.
    1. Bodey F, Hopper I, Krum H. Neprilysin inhibitors preserve renal function in heart failure. Int J Cardiol 2015;179:329–330.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する