Mizuki Akahori1, Surya Ayalasomayajula2, Thomas Langenickel3, Parasar Pal4, Wei Zhou5, Gangadhar Sunkara5. 1. Novartis Pharma K.K., Tokyo, Japan. 2. Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research (NIBR), One Health Plaza, Bldg 436/3014, East Hanover, NJ, 07936, USA. surya.ayalasomayajula@novartis.com. 3. Clinical Pharmacology and Profiling, Translational Medicine, Novartis Pharma AG, Basel, Switzerland. 4. Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India. 5. Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research (NIBR), One Health Plaza, Bldg 436/3014, East Hanover, NJ, 07936, USA.
Abstract
BACKGROUND AND OBJECTIVES:LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. METHODS: This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receivingLCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). RESULTS: Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. CONCLUSION: Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.
RCT Entities:
BACKGROUND AND OBJECTIVES:LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failurepatients with reduced ejection fraction and approved in the US, Europe, and many other countries. METHODS: This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). RESULTS: Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. CONCLUSION: Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.
Authors: Thorir D Bjornsson; John A Wagner; Stephen R Donahue; Dawn Harper; Aziz Karim; Marlene S Khouri; William R Murphy; Kristin Roman; Dennis Schneck; Daryl S Sonnichsen; Dennis J Stalker; Stephen D Wise; Stuart Dombey; Caroline Loew Journal: J Clin Pharmacol Date: 2003-09 Impact factor: 3.126
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