Understanding Mechanisms of Food Effect and Developing Reliable PBPK Models Using a Middle-out Approach.
AAPS J
; 23(1): 12, 2021 01 04.
Article
en En
| MEDLINE
| ID: mdl-33398593
Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on their pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption, which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to predict the effect of food on absorption and to reveal the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach, combining bottom-up in vitro-based predictions with limited top-down fitting of key model parameters for clinical data, can be successfully used to predict the magnitude and direction of food effect when it is predicted poorly by a bottom-up approach. For nefazodone, a mechanistic clearance for the gut and liver was added, for furosemide, an absorption window was introduced, and for aprepitant, the biorelevant solubility was refined using multiple solubility measurements. In all cases, these adjustments were supported by literature data and showcased a rational approach to assess the factors limiting absorption and exposure.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Interacciones Alimento-Droga
/
Mucosa Intestinal
/
Modelos Biológicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
AAPS J
Asunto de la revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Año:
2021
Tipo del documento:
Article
Pais de publicación:
Estados Unidos