Utilization of In Vitro, In Vivo and In Silico Tools to Evaluate the pH-Dependent Absorption of a BCS Class II Compound and Identify a pH-Effect Mitigating Strategy.
Pharm Res
; 36(12): 164, 2019 Oct 21.
Article
en En
| MEDLINE
| ID: mdl-31637544
ABSTRACT
PURPOSE:
To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk.METHODS:
Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human.RESULTS:
Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt.CONCLUSIONS:
The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Simulación por Computador
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Famotidina
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Composición de Medicamentos
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Absorción Intestinal
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Antiulcerosos
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Modelos Biológicos
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Idioma:
En
Revista:
Pharm Res
Año:
2019
Tipo del documento:
Article