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A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH

In this paper, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and, thus, differ in absorption at elevated gastric pH. However, routine...

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Autores principales: Zhu, Hao, Chen, Xiaomei, Ahmed, Mariam, Wang, Yaning, Liu, Qi, Uppoor, Ramana S., Kuemmel, Colleen, Mehta, Mehul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853150/
https://www.ncbi.nlm.nih.gov/pubmed/31169344
http://dx.doi.org/10.1111/cts.12658
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author Zhu, Hao
Chen, Xiaomei
Ahmed, Mariam
Wang, Yaning
Liu, Qi
Uppoor, Ramana S.
Kuemmel, Colleen
Mehta, Mehul
author_facet Zhu, Hao
Chen, Xiaomei
Ahmed, Mariam
Wang, Yaning
Liu, Qi
Uppoor, Ramana S.
Kuemmel, Colleen
Mehta, Mehul
author_sort Zhu, Hao
collection PubMed
description In this paper, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and, thus, differ in absorption at elevated gastric pH. However, routine bioequivalence trials using subjects with normal gastric pH (i.e., ~ 1) may fail to identify these differences because dissolution/absorption profiles of the two formulations at normal gastric pH are similar. In the case of palbociclib, it is confirmedthat the free base and salt formulations showed different absorption in patients with different gastric pH. Significant reduction in drug absorption was observed only in patients with elevated gastric pH using free base formulation. The discovery that the free base had significantly reduced absorption hinged on the inclusion of enough patients with elevated gastric pH to detect a difference in a bioequivalence trial. This raises a concern, as demonstrated through simulation, that dissolution/absorption differences in other formulations could be missed in routine bioequivalence trials. Aside from differences in active pharmaceutical ingredients (APIs), other factors, such as changes in excipients or manufacturing methods, may also lead to exposure differences between formulations at elevated gastric pH. For formulations containing different forms of the same active moiety or the same API and showing different dissolution profiles at elevated pH (i.e., pH ~ 4–6.8), evaluation of bioequivalence with gastric pH modulators (e.g., a H(2) blocker) in addition to routine bioequivalence assessments may help to ensure therapeutic equivalence in patients with elevated gastric pH.
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spelling pubmed-68531502019-12-16 A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH Zhu, Hao Chen, Xiaomei Ahmed, Mariam Wang, Yaning Liu, Qi Uppoor, Ramana S. Kuemmel, Colleen Mehta, Mehul Clin Transl Sci Reviews In this paper, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and, thus, differ in absorption at elevated gastric pH. However, routine bioequivalence trials using subjects with normal gastric pH (i.e., ~ 1) may fail to identify these differences because dissolution/absorption profiles of the two formulations at normal gastric pH are similar. In the case of palbociclib, it is confirmedthat the free base and salt formulations showed different absorption in patients with different gastric pH. Significant reduction in drug absorption was observed only in patients with elevated gastric pH using free base formulation. The discovery that the free base had significantly reduced absorption hinged on the inclusion of enough patients with elevated gastric pH to detect a difference in a bioequivalence trial. This raises a concern, as demonstrated through simulation, that dissolution/absorption differences in other formulations could be missed in routine bioequivalence trials. Aside from differences in active pharmaceutical ingredients (APIs), other factors, such as changes in excipients or manufacturing methods, may also lead to exposure differences between formulations at elevated gastric pH. For formulations containing different forms of the same active moiety or the same API and showing different dissolution profiles at elevated pH (i.e., pH ~ 4–6.8), evaluation of bioequivalence with gastric pH modulators (e.g., a H(2) blocker) in addition to routine bioequivalence assessments may help to ensure therapeutic equivalence in patients with elevated gastric pH. John Wiley and Sons Inc. 2019-08-16 2019-11 /pmc/articles/PMC6853150/ /pubmed/31169344 http://dx.doi.org/10.1111/cts.12658 Text en Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Reviews
Zhu, Hao
Chen, Xiaomei
Ahmed, Mariam
Wang, Yaning
Liu, Qi
Uppoor, Ramana S.
Kuemmel, Colleen
Mehta, Mehul
A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
title A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
title_full A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
title_fullStr A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
title_full_unstemmed A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
title_short A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
title_sort proposal of conducting bioequivalence trials with gastric ph modulators for two oral formulations demonstrating different dissolution profiles at elevated ph
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853150/
https://www.ncbi.nlm.nih.gov/pubmed/31169344
http://dx.doi.org/10.1111/cts.12658
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