title: Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.
abstract: LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Hsiu-Ling
authors.initials: HL
authors.lastname: Hsiao
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Thomas Heiko
authors.initials: TH
authors.lastname: Langenickel
authors.affiliation: Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Greeley
authors.affiliation: Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: John
authors.initials: J
authors.lastname: Roberts
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000613:Aminobutyrates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017311:Amlodipine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001130:Arizona; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077261:Carvedilol; D018592:Cross-Over Studies; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011412:Propanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068756:Valsartan
chemical_list: D000319:Adrenergic beta-Antagonists; D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D002227:Carbazoles; D004232:Diuretics; D004338:Drug Combinations; D011412:Propanolamines; D011480:Protease Inhibitors; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000077261:Carvedilol; D017311:Amlodipine; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: LCZ696; amlodipine; carvedilol; hydrochlorothiazide; pharmacokinetic drug-drug interaction