Population pharmacokinetic model-based IVIVC incorporating active metabolite kinetics: Application to aceclofenac...

This study aimed to establish a population pharmacokinetic model-based in vitro-in vivo correlation (IVIVC) for aceclofenac sustained-release (SR) formulations to predict plasma concentrations of both parent drug and active metabolite, diclofenac. Three SR formulations containing 200 mg aceclofenac with different drug release rates were prepared and characterized for in vitro dissolution using the paddle method. In vivo pharmacokinetics were evaluated in beagle dogs (n = 4 per formulation) following oral administration. Plasma concentrations of aceclofenac and diclofenac were simultaneously quantified using a validated liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed incorporating formulation-dependent Michaelis-Menten dissolution kinetics, time-dependent absorption, and metabolite formation. In vivo dissolution rates estimated from the model were correlated with in vitro dissolution rates to establish a level A IVIVC. An independent formulation was used for external validation. The resulting model successfully described plasma concentration-time profiles of both compounds across all formulations, with logarithmic correlation between in vitro and in vivo dissolution rates demonstrating strong predictability (R² = 0.96). For the external validation formulation, C_max prediction errors were 1.32% and 1.50% for aceclofenac and diclofenac, respectively, while AUC prediction errors were 16.49% and 2.39%. This study successfully established a population pharmacokinetic model-based IVIVC that predicts the pharmacokinetics of both parent drug and active metabolite from in vitro dissolution data. This approach provides a practical framework for developing SR formulations of drugs with active metabolites.