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Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

Lin, Wen and Ji, Tao and Ayalasomayajula, Surya and Hanna, Imad and Heimbach, Tycho and Jarugula, Venkateswar and He, Handan and Lin, Tsu-Han and Breen, Chris (2017) Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model. Journal of Pharmaceutical Science, 105 (5). pp. 1439-1451.

Abstract

Sacubitril/valsartan (LCZ696) is an ARNI, which has been approved for the treatment of patients with heart failure. Sacubitril was identified as an inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3 in vitro. “Statins” are OATP substrates and may be co-administered with LCZ696, thus drug interactions might occur. In a clinical study, LCZ696 increases Cmax and AUC of atorvastatin and its metabolites by 2- and 1.3-fold, respectively. In contrast, LCZ696 did not significantly increase systemic exposure of simvastatin and simvastatin acid. To identify the underlying mechanisms for the different LCZ696 statin drug interactions a PBPKmodel was developed. The PBPK model was constructed by incorporating an in vitro Ki value of sacubitril for OATP1B1 and OATP1B3, and a hybrid simvastatin/simvastatin acid model including OATP-mediated Clint,T. This PBPK model depicted simvastatin acid plasma concentration-time profiles and successfully predicted the lack of a DDI effect. An atorvastatin PBPK model was used in combination with the sacubitril model which simulated the DDI effect of sacubitril on atorvastatin. The simulation of portal vein concentrations indicated that Tmax, T1/2 and Cmax of sacubitril and the short atorvastatin Tmax are critical parameters leading to ~1.7-fold Cmax ratio for atorvastatin. Additionally, for OATP substrates with slow absorption, such as simvastatin acid, no drug interaction is anticipated. Similar mechanisms were applied to evaluate the DDI effect for currently widely prescribed statins via OATP inhibition by sacubitril. Finally, parameter sensitivity analyses results predicted maximally no more than 2-fold exposure increase for various statins which are hepatic OATP substrates

Item Type: Article
Keywords: Physiologically based pharmacokinetic modelling, transporters, statin, absorption, organic anion-transporting polypeptide, drug-drug interaction
Date Deposited: 22 Jul 2017 00:45
Last Modified: 22 Jul 2017 00:45
URI: https://oak.novartis.com/id/eprint/30748

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