mp9b00964_si_001.pdf (1.57 MB)
Pharmacokinetic/Pharmacodynamic Modeling To Predict the Antiplatelet Effect of the Ticagrelor-Loaded Self-Microemulsifying Drug Delivery System in Rats
journal contribution
posted on 2020-02-24, 15:40 authored by Young-Guk Na, Jin-Ju Byeon, Min-Ki Kim, Min-Gu Han, Cheong-Weon Cho, Jong-Suep Baek, Hong-Ki Lee, Young G. ShinTicagrelor
(TCG) has been used as an antiplatelet agent for acute
coronary syndrome 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 PD response of the TCG-loaded
self-microemulsifying drug delivery system (TCG-SME) in rats. Pure
TCG and TCG-SME (2, 5, and 10 mg/kg of TCG) were 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 PK profiles of pure TCG and TCG-SME could be
well-explained with a two-compartment PK model. The accuracy of the
PK model was assessed with a goodness-of-fit plot and conditional
weight residual error (CWRES). Also, the visual predictive check 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 the 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. In addition,
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.