Data from an open-label, fixed-sequence study showed that although sacubitril inhibited organic anion-transporting polypeptides (OATP)1B1 and OATP1B3 in vitro, this did not translate to any clinically relevant in vivo effect. Findings from the study are published in the Journal of Clinical Pharmacy and Therapeutics.
Sacubitril/valsartan (Entresto) was approved by the Food and Drug Administration (FDA) for the treatment of heart failure patients with reduced ejection fraction. Some patients also receive concomitant statins, whose clearance is mediated via OATP1B1/1B3. Researchers from the Novartis Institutes for Biomedical Research evaluated the inhibition of these transporters by sacubitril/valsartan in vitro. Also, a clinical study (n=26) was conducted to determine the effect of Entresto on the exposure of simvastatin and its active metabolite simvastatin acid. In the study, healthy volunteers were given simvastatin 40mg alone or in combination with sacubitril/valsartan or after 1 or 2 hours of sacubitril/valsartan dosing.
Researchers found no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan but sacubitril was found to inhibit OATP1B1/1B3 in vitro. When given concomitantly with simvastatin, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When given 1 hour after sacubitril/valsartan dosing, the Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When given 2 hours after sacubitril/valsartan dosing, the Cmax of simvastatin decreased by 33% and simvastatin acid increased by 16%.
No significant changes were seen in the total exposure (AUCs) of simvastatin or simvastatin acid with concomitant use or time-separated administration with sacubitril/valsartan. The study also showed sacubitril/valsartan and simvastatin were generally well tolerated when given alone or together.
In general, study authors were able to conclude that “no pharmacokinetic drug-drug interaction was observed” when simvastatin was given in combination with sacubitril/valsartan in a clinical setting.
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