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Interactions of everolimus and sorafenib in whole blood lymphocyte proliferation
Dipti K Pawaskar1, Robert M Straubinger, Gerald J Fetterly
1Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA.
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 IC(50) of 4.5 nM for females and 10.5 nM in males. Sorafenib alone caused complete inhibition, with a mean IC(50) 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.
Insights
This study investigated the effects of everolimus and sorafenib on lymphocyte proliferation. The combination showed slight antagonism, suggesting potential for reduced immunosuppression when used together in cancer therapy.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Everolimus (mTOR inhibitor) and sorafenib (multikinase inhibitor) are used in cancer therapy.
- Both drugs individually inhibit lymphocyte proliferation.
- Combination therapy with these agents is under investigation for various cancers.
Purpose of the Study:
- To evaluate the effects of everolimus and sorafenib on lymphocyte proliferation.
- To anticipate potential immunosuppression when these drugs are used in combination.
- To characterize the interaction between everolimus and sorafenib regarding lymphocyte proliferation inhibition.
Main Methods:
- Ex vivo evaluation of lymphocyte proliferation inhibition across a range of drug concentrations.
- Analysis using a population approach and a modified Ariens noncompetitive interaction model.
- Assessment of drug interactions, including effects alone and in combination.
Main Results:
- Everolimus demonstrated partial inhibition (mean IC50: 4.5 nM females, 10.5 nM males).
- Sorafenib showed complete inhibition (mean IC50: 11.4 μM, no gender difference).
- The interaction term suggested slight antagonism between the two drugs.
Conclusions:
- Everolimus and sorafenib exhibit slight antagonism in inhibiting lymphocyte proliferation.
- This antagonism may mitigate potential immunosuppressive effects in combination cancer therapy.
- Further research is warranted to fully understand the clinical implications of this interaction.
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