Pharmacokinetic-pharmacodynamic interactions of everolimus and sorafenib in pancreatic cancer
Pawaskar, Dipti K.
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Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. There are no approved second-line therapies after failure of gemcitabine which is the standard of care, thus giving rise to a need for alternative treatment approaches. Pancreatic cancer is a disease of somatic mutations causing hyperactivation of signaling pathways involved in cell proliferation and survival. Inhibition of a single aberrated signaling pathway using targeted therapies leads to compensatory activation of other related pathways. This observation gave rise to the hypothesis of simultaneously inhibiting two inter-related pathways thus anticipating synergistic effects on tumor growth inhibition. This thesis investigated the pharmacokinetic-pharmacodynamic (PK-PD) interactions of two drugs, everolimus and sorafenib, in pancreatic cancer. The anti-proliferative actions of the two drugs on two pancreatic cancer cell lines exhibited a slight antagonistic interaction when modeled using multiple methods. Inhibition of lymphocyte proliferation, which is an adverse effect of the drugs in cancer therapy, also exhibited an antagonistic interaction between the two drugs when analyzed ex vivo in human blood. Physiologically-based PK (PBPK) models for everolimus and sorafenib in mice from 7 studies well described the concentration time profiles in plasma and tissues including the tumor. Combined administration of the drugs did not alter the PK of either drug, thus proving absence of PK interaction between the drugs. Doses of everolimus and sorafenib that individually caused significant tumor inhibition in pancreatic cancer xenografts were ineffective on xenografts with patient derived tumors individually and in combination. A clinically relevant dose of sorafenib and a higher dose of everolimus inhibited the tumor growth significantly when given alone, and caused complete inhibition of growth when given in combination. The PBPK-PD model developed adequately captured the tumor growth observed in xenografts indicating a highly synergistic pharmacodynamic interaction between the two drugs at appropriate doses. A comparison of results from the preclinical studies to PK and toxicity results from cancer patients in the clinical study combining the two drugs revealed the lack of feasibility of the combination in pancreatic cancer patients at currently approved doses. In summary, this thesis proved the hypothesis of synergistic inhibition of pancreatic cancer tumor growth by concomitant use of everolimus and sorafenib. The bridging of preclinical and clinical results provides leverage for translational approach to drive decisions for future trials in pancreatic cancer patients.