Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.
OBJECTIVE
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 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 Cmaxby 72, 27, and 51 %, respectively.


CONCLUSIONS
Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.
Novartis Pharma K.K., Tokyo, Japan.
Mizuki
M
Akahori
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.
Surya
http://orcid.org/0000-0002-5917-9397
S
Ayalasomayajula
Clinical Pharmacology and Profiling, Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
Thomas
T
Langenickel
Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
Parasar
P
Pal
Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research (NIBR), One Health Plaza, Bldg 436/3014, East Hanover, NJ, 07936, USA.
Wei
W
Zhou
Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research (NIBR), One Health Plaza, Bldg 436/3014, East Hanover, NJ, 07936, USA.
Gangadhar
G
Sunkara
D000328:Adult; D000613:Aminobutyrates / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D001713:Biphenyl Compounds; D004311:Double-Blind Method; D004338:Drug Combinations; D018565:Food-Drug Interactions / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000493:pharmacokinetics*; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000493:pharmacokinetics*; D000068756:Valsartan / Q000493:pharmacokinetics*; D055815:Young Adult
D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination