title: Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.
abstract: Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmaxby 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmaxthat coincide with the low Cmaxof sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Tao
authors.initials: T
authors.lastname: Ji
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Heidi
authors.initials: H
authors.lastname: Einolf
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Surya
authors.initials: S
authors.lastname: Ayalasomayajula
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Tsu-Han
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Imad
authors.initials: I
authors.lastname: Hanna
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Christopher
authors.initials: C
authors.lastname: Breen
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Venkateswar
authors.initials: V
authors.lastname: Jarugula
authors.affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936. Electronic address: handan.he@novartis.com.
authors.forename: Handan
authors.initials: H
authors.lastname: He
mesh_terms: D000613:Aminobutyrates / Q000493:pharmacokinetics*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics; D057911:Angiotensin Receptor Antagonists / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D008954:Models, Biological; D013777:Tetrazoles / Q000493:pharmacokinetics*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: absorption; drug-drug interaction; organic anion-transporting polypeptide; physiologically based pharmacokinetic modeling; statin; transporters