Interactions of everolimus and sorafenib in whole blood lymphocyte proliferation

Purpose: Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of hematopoietic cells by targeting the mammalian target of rapamycin (mTOR). Sorafenib is a multikinase inhibitor that inhibits cell proliferation by arresting cells in the G0-G1 phase of the cell cycle. These agents are under investigation as combination therapy for various cancers. Because the two drugs individually inhibit lymphocyte proliferation, this study examined the effects of everolimus and sorafenib on lymphocyte proliferation in order to anticipate possible immunosuppression. Methods: Inhibition of lymphocyte proliferation was evaluated ex vivo over a range of concentrations of these drugs, alone and in combination. Data analysis, using a population approach to characterize interactions, employed the Ariens noncompetitive interaction model, which was modified to accommodate interactions of the two drugs. Results: Everolimus alone caused partial inhibition of lymphocyte proliferation, with a mean IC₅₀ of 4.5 nM for females and 10.5 nM in males. Sorafenib alone caused complete inhibition, with a mean IC₅₀ of 11.4 μM and no difference between genders. Conclusion: The population estimate for the interaction term was greater than 1, suggesting that the two drugs exert slight antagonism in terms of inhibition of lymphocyte proliferation.