Open AccessPharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan ( LCZ 696) in Patients with Heart Failure and Reduced Ejection Fraction
Author(s) -
Kobalava Zhanna,
Kotovskaya Yulia,
Averkov Oleg,
Pavlikova Elena,
Moiseev Valentine,
Albrecht Diego,
Chandra Priya,
Ayalasomayajula Surya,
Prescott Margaret F.,
Pal Parasar,
Langenickel Thomas H.,
Jordaan Pierre,
Rajman Iris
Publication year - 2016
Publication title -
cardiovascular therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 46
eISSN - 1755-5922
pISSN - 1755-5914
DOI - 10.1111/1755-5922.12183
Subject(s) - sacubitril , medicine , cmax , sacubitril, valsartan , valsartan , ejection fraction , heart failure , neprilysin , pharmacokinetics , pharmacology , endocrinology , pharmacodynamics , cyclic guanosine monophosphate , blood pressure , chemistry , biochemistry , nitric oxide , enzyme
Summary 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 ( HF r EF ). This study assessed the pharmacodynamics and pharmacokinetics of LCZ 696 in patients with HF r EF . Methods This was an open‐label, noncontrolled single‐sequence study. After a 24‐h run‐in period, patients (n = 30) with HF r EF ( EF ≤ 40%; NYHA class II – IV ) received LCZ 696 100 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 [ ACEI s] or angiotensin receptor blockers [ ARB s]). 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 ‐pro BNP 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 LCZ 696, the C max of sacubitril (neprilysin inhibitor prodrug), LBQ 657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100‐ and 200‐mg doses, the C max and AUC 0–12 h for sacubitril and LBQ 657 were approximately dose‐proportional while that of valsartan was less than dose‐proportional. Conclusions Treatment with LCZ 696 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 LCZ 696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.