RESUMEN
A preclinical canine model capable of predicting a compound's potential for a human food effect was developed. The beagle dog was chosen as the in vivo model. A validation set of compounds with known propensities for human food effect was studied. Several diets were considered including high-fat dog food and various quantities of the human FDA meal. The effect of pentagastrin pretreatment was also investigated. The high-fat dog food did not predict human food effect and was discontinued from further evaluation. The amount of FDA meal in the dog was important in the overall prediction of the magnitude of human food effect. Fed/fasted Cmax and AUC ratios using a 50-g aliquot of the FDA meal in the dog were in the closest qualitative agreement to human data. Pentagastrin pretreatment did not affect the AUC in the fed state, but increased the fasted AUC for weakly basic compounds. Pentagastrin pretreatment and a 50-g aliquot of the FDA meal in the dog predicted the human food effect for a validation set of compounds. This model, which is intended for compound screening, will be helpful for determining food effect as a liability when compounds progress from discovery to clinical development.
Asunto(s)
Grasas de la Dieta , Evaluación Preclínica de Medicamentos/métodos , Interacciones Alimento-Droga , Modelos Animales , Pentagastrina/farmacología , Animales , Sulfato de Atazanavir , Disponibilidad Biológica , Perros , Inhibidores de la Proteasa del VIH/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Oligopéptidos/farmacocinética , Pravastatina/farmacocinética , Piridinas/farmacocinéticaRESUMEN
Recently 2 QSPR-based in silico models were developed in our laboratories to predict the aqueous and non-aqueous solubility of drug-like organic compounds. For the intrinsic aqueous solubility model, a set of 321 structurally diverse drugs was collected from literature for the analysis. For the PEG 400 cosolvent model, experimental data for 122 drugs were obtained by a uniform experimental procedure at 4 volume fractions of PEG 400 in water, 0%, 25%, 50%, and 75%. The drugs used in both models represent a wide range of compounds, with log P values from -5 to 7.5, and molecular weights from 100 to >600 g/mol. Because of the standardized procedure used to collect the cosolvent data and the careful assessment of quality used in obtaining literature data, both data sets have potential value for the scientific community for use in building various models that require experimental solubility data.