title: Exploring the Feasibility of Biowaiver Extension of BCS Class III Drugs with Site-Specific Absorption Using Gastrointestinal Simulation Technology.
abstract: OBJECTIVE
  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 (Fa) 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, T85 %= 15-180 min) was performed to predict absorption (maximum concentration, Cmaxand area under the concentration-time curve from time 0 to infinity, AUC0-inf) of the above model/virtual drugs (Fa3.81-80.14 %).
  
  
  RESULTS
  The results of this study indicated that the site-specific absorption and low Famagnified the effect of dissolution rate on Cmaxand AUC0-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 Fa(about >80 %), the biowaiver should extend to rapid dissolution (T85 %= 30 min), and 30 % of Faas the boundary of intermediate permeability class (30 % < Fa< 85 %).
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China.
authors.forename: Le
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics and Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China. sunjin66@21cn.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China. hezhonggui@gmail.com.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D003198:Computer Simulation; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008954:Models, Biological; D010539:Permeability; D050198:Phenoxypropanolamines / Q000378:metabolism*; D012984:Software
chemical_list: D050198:Phenoxypropanolamines