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The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation.
Mol Pharm. 2010 Aug 02; 7(4):1235-43.MP

Abstract

The Biopharmaceutical Classification System (BCS) guidance issued by the FDA allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release (IR) solid oral dosage forms only for BCS class I drugs. However, a number of drugs within BCS class III have been proposed to be eligible for biowaivers. The World Health Organization (WHO) has shortened the requisite dissolution time of BCS class III drugs on their Essential Medicine List (EML) from 30 to 15 min for extended biowaivers; however, the impact of the shorter dissolution time on AUC(0-inf) and C(max) is unknown. The objectives of this investigation were to assess the ability of gastrointestinal simulation software to predict the oral absorption of the BCS class I drugs propranolol and metoprolol and the BCS class III drugs cimetidine, atenolol, and amoxicillin, and to perform in silico bioequivalence studies to assess the feasibility of extending biowaivers to BCS class III drugs. The drug absorption from the gastrointestinal tract was predicted using physicochemical and pharmacokinetic properties of test drugs provided by GastroPlus (version 6.0). Virtual trials with a 200 mL dose volume at different drug release rates (T(85%) = 15 to 180 min) were performed to predict the oral absorption (C(max) and AUC(0-inf)) of the above drugs. Both BCS class I drugs satisfied bioequivalence with regard to the release rates up to 120 min. The results with BCS class III drugs demonstrated bioequivalence using the prolonged release rate, T(85%) = 45 or 60 min, indicating that the dissolution standard for bioequivalence is dependent on the intestinal membrane permeability and permeability profile throughout the gastrointestinal tract. The results of GastroPlus simulations indicate that the dissolution rate of BCS class III drugs could be prolonged to the point where dissolution, rather than permeability, would control the overall absorption. For BCS class III drugs with intestinal absorption patterns similar to those of cimetidine, atenolol or amoxicillin, the dissolution criteria for extension of biowaivers to BCS class III drugs warrants further investigation.

Authors+Show Affiliations

College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20557130

Citation

Tsume, Yasuhiro, and Gordon L. Amidon. "The Biowaiver Extension for BCS Class III Drugs: the Effect of Dissolution Rate On the Bioequivalence of BCS Class III Immediate-release Drugs Predicted By Computer Simulation." Molecular Pharmaceutics, vol. 7, no. 4, 2010, pp. 1235-43.
Tsume Y, Amidon GL. The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation. Mol Pharm. 2010;7(4):1235-43.
Tsume, Y., & Amidon, G. L. (2010). The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation. Molecular Pharmaceutics, 7(4), 1235-43. https://doi.org/10.1021/mp100053q
Tsume Y, Amidon GL. The Biowaiver Extension for BCS Class III Drugs: the Effect of Dissolution Rate On the Bioequivalence of BCS Class III Immediate-release Drugs Predicted By Computer Simulation. Mol Pharm. 2010 Aug 2;7(4):1235-43. PubMed PMID: 20557130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation. AU - Tsume,Yasuhiro, AU - Amidon,Gordon L, PY - 2010/6/19/entrez PY - 2010/6/19/pubmed PY - 2010/12/14/medline SP - 1235 EP - 43 JF - Molecular pharmaceutics JO - Mol Pharm VL - 7 IS - 4 N2 - The Biopharmaceutical Classification System (BCS) guidance issued by the FDA allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release (IR) solid oral dosage forms only for BCS class I drugs. However, a number of drugs within BCS class III have been proposed to be eligible for biowaivers. The World Health Organization (WHO) has shortened the requisite dissolution time of BCS class III drugs on their Essential Medicine List (EML) from 30 to 15 min for extended biowaivers; however, the impact of the shorter dissolution time on AUC(0-inf) and C(max) is unknown. The objectives of this investigation were to assess the ability of gastrointestinal simulation software to predict the oral absorption of the BCS class I drugs propranolol and metoprolol and the BCS class III drugs cimetidine, atenolol, and amoxicillin, and to perform in silico bioequivalence studies to assess the feasibility of extending biowaivers to BCS class III drugs. The drug absorption from the gastrointestinal tract was predicted using physicochemical and pharmacokinetic properties of test drugs provided by GastroPlus (version 6.0). Virtual trials with a 200 mL dose volume at different drug release rates (T(85%) = 15 to 180 min) were performed to predict the oral absorption (C(max) and AUC(0-inf)) of the above drugs. Both BCS class I drugs satisfied bioequivalence with regard to the release rates up to 120 min. The results with BCS class III drugs demonstrated bioequivalence using the prolonged release rate, T(85%) = 45 or 60 min, indicating that the dissolution standard for bioequivalence is dependent on the intestinal membrane permeability and permeability profile throughout the gastrointestinal tract. The results of GastroPlus simulations indicate that the dissolution rate of BCS class III drugs could be prolonged to the point where dissolution, rather than permeability, would control the overall absorption. For BCS class III drugs with intestinal absorption patterns similar to those of cimetidine, atenolol or amoxicillin, the dissolution criteria for extension of biowaivers to BCS class III drugs warrants further investigation. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/20557130/The_biowaiver_extension_for_BCS_class_III_drugs:_the_effect_of_dissolution_rate_on_the_bioequivalence_of_BCS_class_III_immediate_release_drugs_predicted_by_computer_simulation_ L2 - https://doi.org/10.1021/mp100053q DB - PRIME DP - Unbound Medicine ER -