Le Sun1, Jin Sun2, Zhonggui He3. 1. Department of Pharmaceutics, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China. 2. 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. 3. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China. hezhonggui@gmail.com.
Abstract
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, AUC0-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 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 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 %).
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, AUC0-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 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 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 %).
Authors: Marek Drozdzik; Christian Gröer; Jette Penski; Joanna Lapczuk; Marek Ostrowski; Yurong Lai; Bhagwat Prasad; Jashvant D Unadkat; Werner Siegmund; Stefan Oswald Journal: Mol Pharm Date: 2014-09-11 Impact factor: 4.939
Authors: James E Polli; Bertil S I Abrahamsson; Lawrence X Yu; Gordon L Amidon; John M Baldoni; Jack A Cook; Paul Fackler; Kerry Hartauer; Gordon Johnston; Steve L Krill; Robert A Lipper; Waseem A Malick; Vinod P Shah; Duxin Sun; Helen N Winkle; Yunhui Wu; Hua Zhang Journal: AAPS J Date: 2008-08-05 Impact factor: 4.009