Your browser doesn't support javascript.
loading
Analysis of exposure margins in developmental toxicity studies for detection of human teratogens.
Andrews, Paul A; Blanset, Diann; Costa, Priscila Lemos; Green, Martin; Green, Maia L; Jacobs, Abigail; Kadaba, Rajkumar; Lebron, Jose A; Mattson, Britta; McNerney, Mary Ellen; Minck, Daniel; Oliveira, Luana de Castro; Theunissen, Peter T; DeGeorge, Joseph J.
Afiliación
  • Andrews PA; Eisai Inc., Woodcliff Lake, NJ, USA. Electronic address: paul_andrews@eisai.com.
  • Blanset D; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
  • Costa PL; Agência Nacional de Vigilância Sanitária, Brasília, Brazil.
  • Green M; US Food and Drug Administration, Silver Spring, MD, USA.
  • Green ML; Merck & Co, Inc., West Point, PA, USA.
  • Jacobs A; US Food and Drug Administration, Silver Spring, MD, USA.
  • Kadaba R; Health Canada, Ottawa, Ontario, Canada.
  • Lebron JA; Merck & Co, Inc., West Point, PA, USA.
  • Mattson B; Merck & Co, Inc., West Point, PA, USA.
  • McNerney ME; Bristol-Myers Squibb, New Brunswick, NJ, USA.
  • Minck D; US Food and Drug Administration, Silver Spring, MD, USA.
  • Oliveira LC; Agência Nacional de Vigilância Sanitária, Brasília, Brazil.
  • Theunissen PT; CBG-MEB, Utrecht, the Netherlands.
  • DeGeorge JJ; Merck & Co, Inc., West Point, PA, USA.
Regul Toxicol Pharmacol ; 105: 62-68, 2019 Jul.
Article en En | MEDLINE | ID: mdl-30981719
The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics. With regards to human risk assessment practices for developmental toxicity, the analysis showed that, after excluding lenalidomide and pomalidomide data in rats, all available AUC margins at the NOAEL for the induction of malformations or embryofetal lethality were <4-fold of the exposure at the MRHD for all 22 therapeutics. These data support the proposed general approach of increased level of concern for human risk when exposure margins of the NOAEL to the MRHD are <10-fold, reduced concern when the exposure margins are 10- to 25-fold, and minimal concern when the exposure margin is > 25-fold.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Teratógenos / Pruebas de Toxicidad / Medición de Riesgo / Embrión de Mamíferos Tipo de estudio: Diagnostic_studies / Etiology_studies / Guideline / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Regul Toxicol Pharmacol Año: 2019 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Teratógenos / Pruebas de Toxicidad / Medición de Riesgo / Embrión de Mamíferos Tipo de estudio: Diagnostic_studies / Etiology_studies / Guideline / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Regul Toxicol Pharmacol Año: 2019 Tipo del documento: Article Pais de publicación: Países Bajos