In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696).
OBJECTIVE
Sacubitril/valsartan (LCZ696) has been recently approved for the treatment of heart failure (HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication.


METHODS
Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro. Furthermore, an open-label, fixed-sequence clinical study was conducted to determine the effect of LCZ696 on the exposure of simvastatin and its active metabolite simvastatin acid. In this clinical study, 26 healthy subjects received simvastatin 40 mg alone or in combination with LCZ696 or after 1 or 2 h of LCZ696 dosing.


CONCLUSIONS
Although no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan was observed, sacubitril inhibited OATP1B1 and OATP1B3 in vitro, with IC50 of 1·91 and 3·81 μm, respectively. Upon co-administration of simvastatin with LCZ696, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When administered 1 h after LCZ696 dosing, the corresponding Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When administered 2 h after LCZ696 dosing, the Cmax of simvastatin decreased by 33% and that of simvastatin acid increased by 16%. However, no notable changes were observed in the AUCs of simvastatin or simvastatin acid upon co-administration or time-separated administration with LCZ696. No notable impact of simvastatin co-administration was observed on the pharmacokinetics of LCZ696 analytes. LCZ696 and simvastatin were generally well tolerated when administered alone or in combination.


CONCLUSIONS
Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect.
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
S
S
Ayalasomayajula
Translational Medicine, Drug Metabolism and Pharmacokinetics, NIBR, Shanghai, China.
Y
Y
Han
Translational Medicine, Clinical Pharmacology and Profiling, NIBR, Basel, Switzerland.
T
T
Langenickel
CS&I, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
K
K
Malcolm
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
W
W
Zhou
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
I
I
Hanna
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
N
N
Alexander
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
A
A
Natrillo
Biostatistical Sciences, Novartis Healthcare Private Limited, Hyderabad, India.
B
B
Goswami
Translational Medicine, Clinical Pharmacology and Profiling, NIBR, Basel, Switzerland.
M
M
Hinder
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
G
G
Sunkara
D000328:Adult; D000613:Aminobutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors*; D019821:Simvastatin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D000068756:Valsartan; D055815:Young Adult
D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; C000609743:LBQ657; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles; D000068756:Valsartan; C063287:simvastatin acid; D019821:Simvastatin; C549068:sacubitril and valsartan sodium hydrate drug combination
LCZ696; OATP; drug interaction; sacubitril/valsartan; simvastatin