Modeling the synergism between the anti-angiogenic drug sunitinib and irinotecan in xenografted mice
S. Wilson, E. Grenier, M. Wei, V. Calvez, B. You, M. Tod, B. Ribba
INRIA Grenoble Rhone-Alpes, Numed Project Team, 655 avenue de l’Europe, 38330 Montbonnot-Saint-Martin, France
Objectives: We aim to evaluate a potential synergistic effect between sunitinib, an anti-angiogenic agent, when given in combination with irinotecan, a cytotoxic agent, in preclinical settings using tumor inhibition models.
Methods: We analyze a data set consisting of longitudinal tumor size measurements (1,371 total observations) in 90 colorectal tumor-bearing mice. Mice received single or combination administration of sunitinib and/or irinotecan. We model this data with a system of non-linear ordinary differential equations that describe tumor growth and angiogenesis. Sunitinib is modeled as acting by reducing the carrying capacity of the tumor, while irinotecan directly reduces the tumor bulk by inducing progressive cell death through transit compartments. Model parameters corresponding to tumor growth and monotherapy are estimated in a mixed-effect manner using Monolix (Lixoft) while parameters corresponding to drug synergism are estimated in a fixed-effect manner using a Nelder-Mead Simplex Method. We then evaluate the hypothesis that sunitinib and irinotecan interact synergistically when administered together.
Results: Through a chi-squared test on the residuals generated by the single and combination arm simulations, we conclude that there must be a synergistic interaction between these drugs (p<0.0001). We found that this interaction takes place in the rate parameter defining the speed in which cells die once affected by irinotecan, with this speed being proportional to the area under the curve of sunitinib given prior to the first dose of irinotecan. This increase in death rate can be related to re-oxygenation of cells due to the improved vasculature induced by sunitinib. A direct consequence of this interaction is the creation of a therapeutic window in which the relative timing between drug administrations is most effective. Irinotecan administered 5 days after onset of sunitinib administration leads to the maximum relative reduction of tumor size (9.52%).
Conclusions: Our model suggests that synergism between irinotecan and sunitinib is a necessary consideration for future studies. Model dynamics indicate the existence of an optimal timing of irinotecan administration with respect to that of sunitinib. This model can be used as a simulation tool to increase overall treatment efficacy by suggesting protocols based on the identification of optimal treatment windows created by the synergism between anti-angiogenic and chemotherapeutic drugs.