Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.
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 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg 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.
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Lu
L
Gan
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Xuemin
X
Jiang
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Anisha
A
Mendonza
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Therese
T
Swan
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Christine
C
Reynolds
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Joanne
J
Nguyen
Novartis Healthcare Pvt Ltd, Hyderabad, Andhra Pradesh, India.
Parasar
P
Pal
Novartis Healthcare Pvt Ltd, Hyderabad, Andhra Pradesh, India.
Srikanth
S
Neelakantham
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Marion
M
Dahlke
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Thomas
T
Langenickel
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Iris
I
Rajman
Novartis Pharma K.K, Tokyo, Japan.
Mizuki
M
Akahori
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Wei
W
Zhou
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Sam
S
Rebello
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Gangadhar
G
Sunkara
D000293:Adolescent; D000328:Adult; D000613:Aminobutyrates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000068756:Valsartan; D055815:Young Adult
D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; C072593:ethinyl estradiol, levonorgestrel drug combination; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D000068756:Valsartan; D008687:Metformin; D009853:Omeprazole; C549068:sacubitril and valsartan sodium hydrate drug combination
Angiotensin receptor neprilysin inhibitor; Combination oral contraceptive; Drug–drug interaction; LCZ696; Metformin; Omeprazole