LAUSR

Ticagrelor (TCG) has been used as an antiplatelet agent for acute coronary syndrome (ACS) patients. The aim of this research was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model of TCG and to apply the model for predicting the pharmacodynamic (PD) response of ticagrelor-loaded self-microemulsifying drug delivery system (TCG-SME) in rats. Pure TCG and TCG-SME (2, 5, and 10 mg/kg of TCG) was orally administered to male Sprague-Dawley rats. Plasma samples were collected at scheduled time-points and then analyzed for TCG plasma concentrations and antiplatelet effects. The inhibition of platelet aggregation of TCG was measured as a PD response. The pharmacokinetic (PK) profiles of pure TCG and TCG-SME could be well-explained with a two-compartment PK model. The accuracy of PK model was assessed with goodness-of-fit plot and conditional weight residual error (CWRES). Also, the visual predictive check (VPC) was investigated based on the predictions. A population PK/PD model for pure TCG was established as an indirect response Emax model linked to the two-compartment PK model of pure TCG. The PK/PD model proposed a suitable fitting to link the plasma concentration of TCG simultaneously with platelet aggregation. Based on the PK data of TCG-SME, as well as the established PK/PD model of pure TCG, the PD profiles of TCG-SME were simulated. TCG-SME was more effective in inducing antiplatelet effect than pure TCG at equivalent doses of TCG. The accuracy of the simulation was verified by comparing the simulated PD profile with the profile observed in rats. The observations were close to the model simulations. And, the values of CWRES were almost within ± 2. In conclusion, the PK/PD modeling approach can provide a way for predicting mathematically the PD responses from PK profiles of other TCG formulations, and a conceptual prediction for future clinical assessment.