Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects

• Published in: Clinical pharmacology in drug development Vol. 5; no. 1; pp. 27 - 39
• Main Authors: Gan, Lu, Jiang, Xuemin, Mendonza, Anisha, Swan, Therese, Reynolds, Christine, Nguyen, Joanne, Pal, Parasar, Neelakantham, Srikanth, Dahlke, Marion, Langenickel, Thomas, Rajman, Iris, Akahori, Mizuki, Zhou, Wei, Rebello, Sam, Sunkara, Gangadhar
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.01.2016; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Aminobutyrates - administration & dosage; Aminobutyrates - pharmacokinetics; Angiotensin Receptor Antagonists - administration & dosage; Angiotensin Receptor Antagonists - pharmacokinetics; Angiotensin receptor neprilysin inhibitor; Area Under Curve; Combination oral contraceptive; Drug Combinations; Drug Interactions; Drug-drug interaction; Ethinyl Estradiol - administration & dosage; Ethinyl Estradiol - pharmacokinetics; Female; Humans; LCZ696; Levonorgestrel - administration & dosage; Levonorgestrel - pharmacokinetics; Male; Metformin; Metformin - administration & dosage; Metformin - pharmacokinetics; Middle Aged; Omeprazole; Omeprazole - administration & dosage; Omeprazole - pharmacokinetics; Tetrazoles - administration & dosage; Tetrazoles - pharmacokinetics; Young Adult; Omeprazole; Angiotensin receptor neprilysin inhibitor; LCZ696; Metformin; Combination oral contraceptive; Drug–drug interaction
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.181

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug‐drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co‐administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel‐ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open‐label, single‐sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel‐ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co‐administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co‐administration of LCZ696 with levonorgestrel‐ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co‐administration of LCZ696 with omeprazole, metformin, or levonorgestrel‐ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.