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

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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 %).

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Authors and Affiliations

  1. Department of Pharmaceutics and Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China

    Jin Sun

  2. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China

    Zhonggui He

  3. Department of Pharmaceutics, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China

    Le Sun

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  1. Le Sun
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Correspondence to Jin Sun or Zhonggui He.

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Funding

We thank National basic scientific talent training fund projects (No. J1103606), and Technology bureau in Shenyang (No. ZCJJ2013402). We also thank financial support from Project for New Century Excellent Talents of Ministry of Education (No. NCET-12-1015) and the financial support from Doctor start-up foundation of Liaoning Province (No. 20141031).

Conflicts of interest

Le Sun, Jin Sun and Zhonggui He declare no conflicts of interest.

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Sun, L., Sun, J. & He, Z. Exploring the Feasibility of Biowaiver Extension of BCS Class III Drugs with Site-Specific Absorption Using Gastrointestinal Simulation Technology. Eur J Drug Metab Pharmacokinet 42, 471–487 (2017). https://doi.org/10.1007/s13318-016-0361-2

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