Physiologically based Biopharmaceutics Modeling (PBBM) Reveals a Low Dissolution-related Bioequivalence Risk for...

A conservative BCS class III classification was recently proposed for amlodipine based on inconclusive permeability evidence. However, the scarce in vivo data suggest that amlodipine is slowly, though completely, absorbed. This means that the very rapid dissolution criterion associated with a BCS class III classification may be overly restrictive for immediate-release amlodipine products. The aim of this manuscript was to develop and validate a physiologically based biopharmaceutics model (PBBM) to assess the risk of bioequivalence failure associated with dissolution. Given that amlodipine is a lipophilic weak base, the absorption model incorporated a surrogate representation of intracellular lysosomal trapping through the Fu_Ent parameter, resulting in an adequate description of oral pharmacokinetics. Dissolution input included in vitro profiles obtained in phosphate buffer pH 6.8 at 50 rpm for different multisource products, fitted to either the Johnson model or the Z-factor approach. Although several products did not meet biowaiver dissolution criteria, virtual bioequivalence simulations conducted with the validated PBBM consistently predicted bioequivalence across tested formulations. Overall, these findings suggest that dissolution differences would have limited impact on the in vivo performance of amlodipine and support a low dissolution-related bioequivalence risk for immediate-release amlodipine tablets.