title: Assessment of Drug-Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects.
abstract: OBJECTIVE
  LCZ696 (sacubitril/valsartan), a novel angiotensin receptor neprilysin inhibitor has been recently approved for the treatment of patients with heart failure (HF) and reduced ejection fraction. As several HF patients are likely to use statins as co-medications, the potential for a pharmacokinetic drug-drug interaction between atorvastatin and LCZ696 was evaluated.
  
  
  METHODS
  This was an open-label, three-period, single-sequence study in 28 healthy Chinese male subjects wherein LCZ696 200 mg was administered twice daily for 5 days in period 1. Following a washout period, atorvastatin 80 mg was administered once daily for 4 days (period 2) and subsequently co-administered with LCZ696 200 mg for 5 days (period 3). Serial plasma samples were collected to determine pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan) and atorvastatin and its metabolites.
  
  
  RESULTS
  Atorvastatin co-administration had no effect on the pharmacokinetics of LBQ657, while the AUCτ,ssand Cmax,ssof sacubitril increased by 30 and 19 %, respectively, and the corresponding values for valsartan decreased by 19 and 9 %, respectively. Co-administration with LCZ696 increased Cmax,ssof atorvastatin, o-hydroxyatorvastatin, and p-hydroxyatorvastatin by 74, 68, and 108 %, respectively, and the AUCτ,ssof corresponding analytes increased by 34, 22, and 26 %, respectively.
  
  
  CONCLUSIONS
  While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the Cmaxof atorvastatin and its metabolites increased twofold, with a marginal increase in AUC (<1.3-fold). Multiple-dose administration of LCZ696 200 mg twice daily and atorvastatin 80 mg once daily either alone or in combination was generally safe and well tolerated in healthy subjects.
authors.affiliation: 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: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: Clinical Sciences and Innovation, Novartis Institutes for Biomedical Research, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langenickel
authors.affiliation: Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
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, Basel, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
mesh_terms: D000328:Adult; D000613:Aminobutyrates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D044466:Asian People; D000069059:Atorvastatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D002681:China; D004338:Drug Combinations; D004347:Drug Interactions; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000924:Anticholesteremic Agents; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D000069059:Atorvastatin; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination