(T1130-04-25) Extended In Vitro-In Vivo Correlation (IVIVC) Model to Predict the Pharmacokinetics of Ticagrelor Sustained-Release Formulations

Purpose: In vitro-in vivo correlation (IVIVC) is a mathematical relationship between an in vitro attribute and the in vivo performance of sustained-release (SR) formulations (1). As a new mathematical model to correlate the formulation, in vitro dissolution, and in vivo pharmacokinetics, a novel extended IVIVC has been developed (2, 3). This study aimed to apply the extended IVIVC model to predict the pharmacokinetics of ticagrelor SR formulations from their formulation compositions.

Methods: A total of thirteen ticagrelor SR tablets with different drug release rates were designed by applying the design of the experiment (DoE) method and prepared by the wet granulation. The in vitro dissolution was determined by the paddle method. The obtained in vitro drug release profiles were described by Michaelis-Menten kinetics. An additional five ticagrelor SR tablets were prepared to validate the DoE model. In vivo pharmacokinetics of three types of ticagrelor SR tablets (10 mg per tablet) with different dissolution rates were evaluated in Beagle dogs (n=4 each). To characterize the pharmacokinetics of ticagrelor SR tablets, a population pharmacokinetic model was developed. Finally, an extended IVIVC model has been established by connecting the DoE, in vitro drug release, and in vivo pharmacokinetics.

Results: The DoE model describing the effects of the SR formulation compositions on the dissolution parameters, i.e., the time of 80% dissolution (T80), the maximum release rate based on Michaelis-Menten kinetics (Vmax), was derived. The average prediction error (PE%) of the DoE model was 6.15% for T80 and 1.98% for Vmax. The population pharmacokinetic model incorporated the time-dependent dissolution and successfully described the in vivo pharmacokinetics of ticagrelor SR tablets after oral administration in Beagle dogs. Finally, the extended IVIVC model was established by connecting the mathematical equation from DoE, in vitro dissolution, and in vivo pharmacokinetics. The extended IVIVC model allowed for predicting the in vivo pharmacokinetics of ticagrelor SR tablets from the formulation composition as an input. Compared to the observed values, the average PE% of the extended IVIVC model was 4.26% for Cmax and 8.27% for AUC.

Conclusion: This study demonstrated the utility of the extended IVIVC model for the prediction of the impact of formulation changes on the in vivo pharmacokinetics by using ticagrelor as a model drug. The extended IVIVC model may provide a valuable tool for the successful development of SR formulations to achieve the desired pharmacokinetic profile.

References: 1. US FDA. Guidance for Industry, Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations 1997.
2. Lim JY, Kim TH, Song CH, Kim DH, Shin BS, Shin S. Novel extended IVIVC combined with DoE to predict pharmacokinetics from formulation compositions. J Control Release. 2022;343:443-56.
3. Lee DY, Shin S, Kim TH, Shin BS. Establishment of Level a In Vitro-In Vivo Correlation (IVIVC) via Extended DoE-IVIVC Model: A Donepezil Case Study. Pharmaceutics. 2022;14(6).

Acknowledgements:This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Nos. NRF-2021R1A2B5B01001970 and NRF-2023R1A2C1007013).