RESUMEN
BACKGROUND AND OBJECTIVE: When eye diseases are treated by topical administration, the success of treatment lies in the effective drug concentration in the target tissue. This is why the drug's pharmacokinetic, in the different substructures of the eye, needs to be explored more accurately during drug development. The aim of the present analysis was to describe by rabbit model, the distribution of a drug after ocular instillation in the selected eye tissues and fluids. METHODS: By a top-down population approach, we developed and validated a population pharmacokinetics (PopPK) model, using tissue concentrations (tear, naso-lacrymal duct, cornea and aqueous humor) of a new src tyrosine kinase inhibitor (FV-60165) in each anterior segment's tissue and fluid of the rabbit eye. Inter-individual variability was estimated and the impact of the formulation (solution or nanosuspension) was evaluated. RESULTS: The model structure selected for the eye is a 4-compartment model with the formulation as a significant covariate on the first-order rate constant between tears and the naso-lacrymal duct. The model showed a good predictive performance and may be used to estimate the concentration-time profiles after single or repeated administration, in each substructure of the eye for each animal included in the analysis. CONCLUSIONS: This analysis allowed describing the distribution of a drug in the different selected tissues and fluids in the rabbit's eyes after instillation of the prodrug as a solution or nanosuspension.
Asunto(s)
Administración Tópica , Ojo/metabolismo , Modelos Biológicos , Profármacos/administración & dosificación , Profármacos/farmacocinética , Animales , Humor Acuoso/metabolismo , Córnea/metabolismo , Conducto Nasolagrimal/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Conejos , Soluciones , Suspensiones , Lágrimas/metabolismo , Distribución TisularRESUMEN
Starting from 11ß-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11ß-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.