title: Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction.
abstract: OBJECTIVE
  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.
authors.affiliation: Center of Applied Clinical Pharmacology, Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Kobalava
authors.affiliation: Center of Applied Clinical Pharmacology, Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kotovskaya
authors.affiliation: Center of Applied Clinical Pharmacology, Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Oleg
authors.initials: O
authors.lastname: Averkov
authors.affiliation: Center of Applied Clinical Pharmacology, Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Pavlikova
authors.affiliation: Center of Applied Clinical Pharmacology, Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Valentine
authors.initials: V
authors.lastname: Moiseev
authors.affiliation: Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Diego
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetic/Pharmacodynamics, Novartis Institute for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Chandra
authors.affiliation: Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetic/Pharmacodynamics, Novartis Institute for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Surya
authors.initials: S
authors.lastname: Ayalasomayajula
authors.affiliation: Clinical Development and Medical Affairs, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Prescott
authors.affiliation: Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Langenickel
authors.affiliation: Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Jordaan
authors.affiliation: Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
mesh_terms: D000368:Aged; D000450:Aldosterone / Q000097:blood; D000613:Aminobutyrates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds; D002908:Chronic Disease; D004334:Drug Administration Schedule; D004338:Drug Combinations; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D012426:Russia; D013318:Stroke Volume; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D000068756:Valsartan; D016277:Ventricular Function, Left
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D015415:Biomarkers; D001713:Biphenyl Compounds; D004338:Drug Combinations; D019332:Endothelin-1; D010446:Peptide Fragments; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000450:Aldosterone; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Heart failure; LCZ696; Pharmacodynamics; Pharmacokinetics; Sacubitril/valsartan