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2016 ; 34
(4
): 191-8
Nephropedia Template TP
gab.com Text
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Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in
Patients with Heart Failure and Reduced Ejection Fraction
#MMPMID26990595
Kobalava Z
; Kotovskaya Y
; Averkov O
; Pavlikova E
; Moiseev V
; Albrecht D
; Chandra P
; Ayalasomayajula S
; Prescott MF
; Pal P
; Langenickel TH
; Jordaan P
; Rajman I
Cardiovasc Ther
2016[Aug]; 34
(4
): 191-8
PMID26990595
show ga
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.