Virtual bioequivalence-guided PBBM prediction for ibuprofen/diphenhydramine citrate tablets: impact of dissolution variability and clinical standard development
TL;DR
This study provides a product-specific, model-informed workflow for bioequivalence risk assessment of ibuprofen/diphenhydramine citrate tablets and offers guidance for quantitative BE risk assessment, thereby holding promise to accelerate the development process while reducing associated costs.
Abstract
This study aimed to integrate in vitro dissolution testing, in vivo pharmacokinetic (PK) studies, and computational simulation to develop a physiologically based biopharmaceutics model (PBBM) for fixed-dose combination ibuprofen/diphenhydramine citrate tablets, thereby evaluating bioequivalence (BE) and establishing a dissolution safe space. Initially, a PBBM model was constructed using B2O Simulator software. Subsequently, an integrated approach was employed, combining dissolution profiles with physiological parameters to develop a virtual bioequivalence (VBE) model. Through simulations involving virtual batches exhibiting diverse dissolution characteristics, the safe dissolution range was determined. Consequently, the PBBM models for ibuprofen and diphenhydramine were successfully validated. Furthermore, the VBE model demonstrated favorable bioequivalence, with an absolute average fold error (AAFE) of less than 1.5 between predicted and observed values for key PK parameters (Cmax and AUC). Scenario analyses supported a formulation- and medium-specific dissolution criterion of no less than 85% dissolution within 30 min for both APIs in pH 6.5 phosphate buffer. Additionally, scenario analyses suggested that, within the simulated two-treatment, two-period crossover settings evaluated in this study, a sample size of approximately 40 subjects may represent a practical lower bound for obtaining stable BE conclusions. In conclusion, this study provides a product-specific, model-informed workflow for bioequivalence risk assessment of ibuprofen/diphenhydramine citrate tablets. The application of PBBM and VBE modeling offers guidance for quantitative BE risk assessment, thereby holding promise to accelerate the development process while reducing associated costs. (The bioequivalence study in healthy subjects was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University [ChiCTR registration number: ChiCTR2500106504; approved: March 12, 2023].)
