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The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.
Martinez, Marilyn N; Fahmy, Raafat; Li, Linge; Herath, Kithsiri; Hollenbeck, R Gary; Ibrahim, Ahmed; Hoag, Stephen W; Longstaff, David; Gao, Shasha; Myers, Michael J.
Afiliación
  • Martinez MN; US Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drugs, Rockville, MD, 20855, US. marilyn.martinez@fda.hhs.gov.
  • Fahmy R; US Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drugs, Rockville, MD, 20855, US.
  • Li L; US Food and Drug Administration, Center for Veterinary Medicine, Office of Applied Sciences, Laurel, MD, 20708, US.
  • Herath K; School of Pharmacy, University Maryland Baltimore, Baltimore, MD, 21201, US.
  • Hollenbeck RG; School of Pharmacy, University Maryland Baltimore, Baltimore, MD, 21201, US.
  • Ibrahim A; School of Pharmacy, University Maryland Baltimore, Baltimore, MD, 21201, US.
  • Hoag SW; School of Pharmacy, University Maryland Baltimore, Baltimore, MD, 21201, US.
  • Longstaff D; US Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drugs, Rockville, MD, 20855, US.
  • Gao S; US Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drugs, Rockville, MD, 20855, US.
  • Myers MJ; US Food and Drug Administration, Center for Veterinary Medicine, Office of Applied Sciences, Laurel, MD, 20708, US.
Pharm Res ; 2024 Sep 09.
Article en En | MEDLINE | ID: mdl-39251485
ABSTRACT

PURPOSE:

Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies.

METHODS:

Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics. Because these APIs are highly permeable, plasma drug concentrations served as a biomarker of in vivo dissolution. Tablets were administered to 27 healthy Beagle dogs (3-way crossover) and the rate and extent of exposure of each API for each formulation was compared in a pairwise manner. These results were compared to product relative in vitro dissolution profiles in 3 media. In vivo and in vitro BE predictions were compared.

RESULTS:

In vivo/in vitro inconsistencies in product relative performance were observed with both compounds when considering product performance across the 3 dissolution media. Formulation comparisons flagged major differences that could explain this outcome.

CONCLUSIONS:

The finding of an inconsistent in vivo/in vitro relationship confirmed that in vitro dissolution alone cannot assure product BE for veterinary locally acting GI products. However, when combined with a comparison of product composition and manufacturing method, this totality of evidence approach can successfully alert scientists to potential therapeutic inequivalence, thereby supporting FDA's efforts to Replace, Reduce, and/or Refine terminal animal studies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Pharm Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Pharm Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos