Physiologically based pharmacokinetic (PBPK) modeling of everolimus (RAD001) in rats involving non-linear tissue uptake.

Everolimus is a novel macrolide immunosuppressant developed for the prophylaxis of allogeneic renal or cardiac transplant rejection. Treatments with immunosuppressants are often associated with organ toxicity that is linked to high organ exposure. Therefore, gaining insight into the pharmacokinetics of everolimus in various organs is highly desirable especially those organs of therapeutic interest or those that pose safety concerns. The aim of this work was to characterize the disposition kinetics of everolimus in rats by physiologically based pharmacokinetic (PBPK) modeling. Blood and tissue samples were collected from male Wistar rats over 24 hr following intravenous (iv) bolus and iv infusion of 1 mg/kg and 10 mg/kg/2 hr of everolimus. Further blood samples were collected between 1 and 170 hr from a third group of rats, which received iv infusion of 1 mg/kg/2 hr of everolimus. Drug concentrations in blood and tissues were determined by a liquid chromatography reverse dilution method. Distribution of everolimus between blood fractions was determined in vitro at 37 degrees C. The results of the study demonstrated that everolimus exhibited moderate non-linear binding to red blood cells. Also, the tissue-to-blood concentration ratio decreased in all tissues as blood concentration increased. A PBPK model involving non-linear tissue binding was able to successfully describe the observed data in blood and all the organs investigated. The highest binding potential was observed in thymus, lungs, and spleen with the greatest tissue affinity observed in thymus, skin, and muscle as compared to other tissues. Everolimus exhibited a high clearance rate that was limited to the hepatic blood flow (47.2 ml/min/kg). The PBPK model was also able to predict the venous blood concentration reasonably well following oral administration. The oral bioavailability value, as estimated with the PBPK, was 12% and was similar to the value obtained by non-compartmental analysis. In conclusion, A PBPK model has been developed that successfully predicts the time course of everolimus in blood and a variety of organs. This model takes into account the non- linear binding of everolimus to red blood cells and tissues. This model may be used to predict everolimus concentration-time course in organs from other species including humans.