Development of a Universal In Vivo Predictive Dissolution Method for a Borderline BCS III/IV Drug Guided by Modeling and Simulations─Acyclovir as a Case Study.

Establishing in vivo predictive dissolution (IPD) conditions requires the consideration of biopredictive aspects during dissolution. For acyclovir, lower dose strengths (200 and 400 mg) can dissolve completely in the gastrointestinal fluids. However, luminal concentrations after administering the highest strength (800 mg) exceed the BCS solubility threshold. Given its poor permeability, sink conditions are not granted for the highest strength. In this study, a universal IPD method for acyclovir tablets was developed using the mini-vessel/mini-paddle apparatus. Computational simulations in a physiologically based pharmacokinetic (PBPK) model further guided the development. Apparatuses with different volumes and stirring conditions were explored, and results served as input for the model. Dissolution of 800 mg of acyclovir tablets in 900 mL of medium largely overpredicted observed plasma profiles due to poor resemblance of nonsink conditions in the lumen. Conversely, dissolution in the mini-vessel filled with 135 mL of HCl, pH 2.0, at 150 rpm, produced accurate predictions of plasma profiles, without affecting previous successful predictions with the lowest strength tablets. Furthermore, in-human and virtual bioequivalence studies confirmed the predictive potential of this method. Therefore, the aforementioned dissolution conditions can be considered as a universal IPD method for acyclovir immediate-release tablets.