Abstract 27: Physiologically based pharmacokinetic model for interactions of sorafenib and everolimus in mice

Objectives:1. To characterize the pharmacokinetics of a combination of an mTOR inhibitor (Everolimus) and a multi- kinase inhibitor (Sorafenib) and 2. To develop a physiologically based pharmacokinetic (PBPK) model for analysis of sorafenib-everolimus interactions. Rationale: Everolimus is an orally administered inhibitor of mTOR (mammalian target of rapamycin), which acts as a cellular sensor for nutrients and growth and drives important processes such as cell proliferation, cell survival and angiogenesis. Sorafenib is an oral small molecule inhibitor of multiple kinases that support tumor progression, and vascular endothelial growth factor (VEGF). The two drugs in combination are being assessed for therapy of pancreatic cancer due to their inhibitory actions on compensatory pathways. Methods: Male Balb/c mice were divided into three groups of 18 animals each. Group 1 was administered everolimus, Group 2 was administered sorafenib and Group 3 was administered both in combination. The drugs were formulated as a microemulsion and administered by oral gavage. Three animals were sacrificed at each of six time points over 24 hours. Plasma, pancreas, muscle, skin, tumor, kidney, lung, brain, spleen, gastrointestinal tract, liver and fat were analyzed for drug concentrations using a validated LC/MS/MS assay. PBPK models were developed for both drugs using ADAPT 5. Results: Everolimus concentrations peaked at 1 hr (Tmax) in plasma and at 0.5-6 hr in various tissues. The half life of everolimus in plasma was 8 hr and that in the tissues analyzed was in the range 10- 16 hr. Sorafenib showed peak concentrations at 1 hr in plasma and ranged from 1-10 hr in the tissues. Sorafenib plasma and tissue concentration-time profiles suggested the existence of a secondary peak at 6 hr, potentially due to enterohepatic recycling. The half life of sorafenib in plasma was 6 hr and was in the range of 4-6 hr in the tissues analyzed. The Kp value, which is a measure of drug concentration in tissue relative to concentration in plasma, was high in pancreas, liver, kidneys, spleen, and GI tract for both the drugs, and represented a high tissue partitioning ratio. The PK of the two drugs did not change when administered concurrently. The PBPK model developed, which included an additional enterohepatic circulation component, reasonably captured the observed data in plasma and in tissues. Conclusion: Combined inhibition of the mTOR and VEGF molecular pathways may improve the efficacy of targeted agents, although the correct dosing strategy for combining these agents is unknown. With the successful development of a PBPK model of the two agents combined, a basis is established for evaluating the efficacy of different drug combination dosing strategies in murine human tumor explant models, to provide insights that will support an ongoing clinical trial of these agents in advanced malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 27. doi:10.1158/1538-7445.AM2011-27