ScholarWorks@중앙대학교

초록

in vitro-in vivo correlation (IVIVC) is a predictive mathematical model that correlates the in vitro dissolution of a dosage form and the corresponding in vivo pharmacokinetics. This study aimed to develop an extended IVIVC model combined with the design of experiment (DoE) that allows the prediction of the pharmacokinetics of a dosage form from its formulation composition, and vice versa. Semaglutide, a potent glucagon-like peptide 1 (GLP-1) receptor agonist, was used as a model drug. The formulations of semaglutide sustained-release (SR) injections with different release rates were designed by applying the mixture design. The in vitro release profiles were determined using the test tube method. The maximum dissolution rates based on Michaelis-Menten kinetics (Vmax) were obtained to describe the effects of the sustained-release injectable formulations. in vivo pharmacokinetics of three types of semaglutide SR injectable formulations (0.2 mg per injection) with different release rates were characterized in SD rats. Plasma concentrations of semaglutide were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. A population pharmacokinetic model was developed to estimate the in vivo dissolution profiles of semaglutide SR injections. By correlating the observed in vitro dissolution parameters and a pharmacokinetic model-estimated in vivo dissolution parameters, level A IVIVC was established for semaglutide SR injectable formulations. Finally, by connecting the DoE model and IVIVC model, the extended IVIVC model has been established. The prediction error (%) of the extended IVIVC model was 1.00% to 4.95% for Cmax and 0.90% to 2.59% for AUC. The present model-based approach would provide a promising tool for more efficient and rational development of drug formulations to acquire an optimal pharmacokinetic profile.