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Identification of solubility-limited absorption of oral anticancer drugs using PBPK modeling based on rat PK and its relevance to human.
Fink, Christina; Lecomte, Marc; Badolo, Lassina; Wagner, Knut; Mäder, Karsten; Peters, Sheila-Annie.
Afiliación
  • Fink C; Chemical Pharmaceutical Development, Merck KGaA, Darmstadt, Germany; Institute of Pharmacy, Faculty of Biosciences, Martin-Luther University Halle-Wittenberg, Germany.
  • Lecomte M; NCE DMPK, Discovery Technology, Merck KGaA, Darmstadt, Germany.
  • Badolo L; NCE DMPK, Discovery Technology, Merck KGaA, Darmstadt, Germany.
  • Wagner K; Chemical Pharmaceutical Development, Merck KGaA, Darmstadt, Germany.
  • Mäder K; Institute of Pharmacy, Faculty of Biosciences, Martin-Luther University Halle-Wittenberg, Germany.
  • Peters SA; Quantitative Pharmacology, Merck KGaA, Darmstadt, Germany. Electronic address: sheila-annie.peters@merckgroup.com.
Eur J Pharm Sci ; 152: 105431, 2020 Sep 01.
Article en En | MEDLINE | ID: mdl-32562690
Solubility is one of the key parameters that is optimized during drug discovery to ensure sufficient drug concentration in systemic circulation and to achieve the desired pharmacological response. We recently reported the application of PBPK analysis of early clinical pharmacokinetic data to identify drugs whose absorption are truly limited by solubility. In this work, we selected ten anticancer drugs that exhibit poor in vitro solubility to explore the utility of this approach to identify solubility-limited absorption based on rat pharmacokinetic data and compare the findings to human data. Oral rat pharmacokinetic studies were performed at the body weight-scaled doses of the model drugs' human food effect studies, and analyzed using a top-down PBPK modeling approach. A good correlation of solubility-limited absorption in rat and human was observed. These results allow an early identification of drugs with truly solubility-limited absorption, with the potential to guide decisions and save valuable resources in drug development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Desarrollo de Medicamentos / Modelos Biológicos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Desarrollo de Medicamentos / Modelos Biológicos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Países Bajos