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

Gan, Lu and Jiang, Xuemin and Mendonza, Anisha and Swan, Therese and Reynolds, Christine and Nguyen, Joanne and Pal, Parasar and Neelakantham, Srikanth Raju and Dahlke, Marion and Langenickel, Thomas Heiko and Rajman, Iris and Akahori, Mizuki and Zhou, Wei and Rebello, Sam and Sunkara, Gangadhar (2016) Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects. Clinical Pharmacology in Drug Development, 5 (1). pp. 27-39. ISSN 2160-7648

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 (400mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40mg q.d. (n=28) or metformin 1000mg q.d. (n=27) or levonorgestrel-ethinyl estradiol 150/30μg 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.

Item Type: Article
Keywords: Angiotensin receptor neprilysin inhibitor Combination oral contraceptive Drug-drug interaction LCZ696 Metformin Omeprazole
Date Deposited: 21 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/22954

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