title: Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.
abstract: OBJECTIVE
  Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects.
  
  
  METHODS
  In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study.
  
  
  RESULTS
  Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (Tmax) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and maximum plasma concentration (Cmax) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects.
  
  
  CONCLUSIONS
  The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA. surya.ayalasomayajula@novartis.com.
authors.forename: Surya
authors.initials: S
authors.lastname: Ayalasomayajula
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Shanghai, China.|Shanghai Roche Pharmaceuticals Ltd., Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yaozong
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langenickel
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Hinder
authors.affiliation: Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Sampath
authors.initials: S
authors.lastname: Kalluri
authors.affiliation: Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Translational Medicine, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
mesh_terms: D000293:Adolescent; D000328:Adult; D000613:Aminobutyrates / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011355:Prodrugs; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination