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

Abstract

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.

• Authors: Lu Gan, Xuemin Jiang, Anisha Mendonza, Therese Swan, Christine Reynolds, Joanne Nguyen, Parasar Pal, Srikanth Neelakantham, Marion Dahlke, Thomas Langenickel, Iris Rajman, Mizuki Akahori, Wei Zhou, Sam Rebello, Gangadhar Sunkara
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 5 Issue 1 Pg. 27-39 (Jan 2016) ISSN: 2160-7648 [Electronic] United States
• PMID: 27119576 (Publication Type: Controlled Clinical Trial, Journal Article)
• Copyright: © 2015, The American College of Clinical Pharmacology.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Drug Combinations
• Tetrazoles
• ethinyl estradiol, levonorgestrel drug combination
• Ethinyl Estradiol
• Levonorgestrel
• Valsartan
• Metformin
• Omeprazole
• sacubitril and valsartan sodium hydrate drug combination

Topics

• Adolescent
• Adult
• Aminobutyrates (administration & dosage, pharmacokinetics)
• Angiotensin Receptor Antagonists (administration & dosage, pharmacokinetics)
• Area Under Curve
• Biphenyl Compounds
• Drug Combinations
• Drug Interactions
• Ethinyl Estradiol (administration & dosage, pharmacokinetics)
• Female
• Humans
• Levonorgestrel (administration & dosage, pharmacokinetics)
• Male
• Metformin (administration & dosage, pharmacokinetics)
• Middle Aged
• Omeprazole (administration & dosage, pharmacokinetics)
• Tetrazoles (administration & dosage, pharmacokinetics)
• Valsartan
• Young Adult