Exploring the Feasibility of Biowaiver Extension of BCS Class III Drugs with Site-Specific Absorption Using Gastrointestinal Simulation Technology

Background and Objectives The US Food and Drug Administration, World Health Organization and European Medicines Agency have allowed biowaiver for some BCS class III drugs, but shortened the requisite dissolution time of BCS class III drugs from 30 to 15 min, considering their site-specific absorption and others risk. The objective of this study was to assess the effects of site-specific absorption, low absorbed fraction (F-a) and gastric emptying rate on the biowaiver extension of BCS class III drugs. Methods The oral absorption of BCS class III drugs nadolol, acebutolol and atenolol which were P-gp substrates, was simulated using GastroPlus software with physiological parameters reflecting site-specific and site-independent absorption. Then, the simulation results were compared with the experimental data in literature. Simulation with different dissolution rates (> 85 % solubility, T-85 % = 15-180 min) was performed to predict absorption (maximum concentration, C-max and area under the concentration-time curve from time 0 to infinity, AUC(0-inf)) of the above model/virtual drugs (F-a 3.81-80.14 %). Results The results of this study indicated that the site-specific absorption and low F-a magnified the effect of dissolution rate on C-max and AUC(0-inf). However, the oral absorption of model drugs was not sensitive to the change of gastric emptying rate from 0.1, 0.25, 0.5 to 1 h. Conclusions Based on the results of this study, we suggest that for BCS class III drug with high F-a (about > 80 %), the biowaiver should extend to rapid dissolution (T-85 % = 30 min), and 30 % of F-a as the boundary of intermediate permeability class (30 % < F-a < 85 %).