Prediction of Ticagrelor and its Active Metabolite in Liver Cirrhosis Populations Using a Physiologically Based Pharmacokinetic Model Involving Pharmacodynamics

Abstract

Ticagrelor, a P2Y12 receptor antagonist, has been highly recommended for use in acute coronary syndrome. The major active metabolite (AM) is similar to the parent drug, which exhibits antiplatelet activity. The inhibition of platelet aggregation (IPA) is used as an assay to demonstrate the anticoagulant efficacy of ticagrelor. In this study, we developed a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of ticagrelor and its AM and combined this model with a pharmacodynamics model to reflect potential pharmacodynamic alterations in liver cirrhosis populations. The simulated results obtained using the PBPK model were validated by fold error values, which were all smaller than 2. Comparisons of exposure in different classifications of liver cirrhosis indicated that exposure to ticagrelor increased significantly with an increase in the degree of cirrhosis severity, whereas exposure to AM was decreased. The total concentration of ticagrelor and AM was related to the IPA included in the Sigmoid Emax model. The PBPK model of ticagrelor and AM could predict the pharmacokinetics of all populations, and a combination of PD models was used to extrapolate for predicting unknown scenarios. Liver cirrhosis may result in prolonged IPA, depending on the severity degree of this disease. The combined PBPK model including IPA can reveal changes in pharmacokinetics and pharmacodynamics in populations affected by liver cirrhosis and indicate the risk potential.