Gan, Lu, Jiang, Xuemin, Mendonza, Anisha, Swan, Therese, Reynolds, Christine, Nguyen, Joanne, Pal, Parasar, Neelakantham, Srikanth Raju, Dahlke, Marion, Langenickel, Thomas Heiko, Rajman, Iris, Akahori, Mizuki, Zhou, Wei, 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