Modeling and predicting optimal treatment scheduling between the antiangiogenic drug sunitinib and irinotecan in preclinical settings

Abstract

We present a system of nonlinear ordinary differential equations used to quantify the complex dynamics of the interactions between tumor growth, vasculature generation, and antiangiogenic treatment. The primary dataset consists of longitudinal tumor size measurements (1,371 total observations) in 105 colorectal tumor-bearing mice. Mice received single or combination administration of sunitinib, an antiangiogenic agent, and/or irinotecan, a cytotoxic agent. Depending on the dataset, parameter estimation was performed either using a mixed-effect approach or by nonlinear least squares. Through a log-likelihood ratio test, we conclude that there is a potential synergistic interaction between sunitinib when administered in combination with irinotecan in preclinical settings. Model simulations were then compared to data from a follow-up preclinical experiment. We conclude that the model has predictive value in identifying the therapeutic window in which the timing between the administrations of these two drugs is most effective.

Figure 1

Mean tumor diameter time course in HT‐29 xenografted mice treated with sunitinib 40 mg/kg daily for 12 days (filled circles) or placebo (empty circles) in Experiment 1.

Figure 2

Sunitinib monotherapy model simulations. (a) Model simulation using average parameters. (b) Visual predictive check showing the 95% confidence interval generated by model simulation (dashed lines) and the tumor size data (circles) for the two experiment arms described in Table S1.

Figure 3

Schematic representation of sunitinib‐irinotecan combination model. Inclusion of the dashed line represents the final model in which the two drugs interact, while exclusion of this line represents a model in which irinotecan and sunitinib are assumed to act independently of each other.

Figure 4

Experiment 2. A comparison of the predictions of the noninteraction and interaction models. (a) Comparison of the simulations of both the noninteraction and interaction models along with the data of Group 4 (combination sunitinib with irinotecan on day 2). (b) Comparison of the simulations of both the noninteraction and interaction models along with the data of Group 5 (combination sunitinib with irinotecan on day 15). (c) Observed tumor sizes vs. the simulated tumor sizes for the noninteraction model. (d) Observed tumor sizes vs. the simulated tumor sizes for the interaction model.

Figure 5

Numerical simulation of Experiment 2 (Supplementary Table S2). Simulations are the result of the interaction model. The five arms to this experiment are as follows: control (black), sunitinib monotherapy (blue), irinotecan monotherapy (red), and two combination protocols. Group 4 (green) involves sunitinib being given once daily for 12 days, with a single dose of irinotecan at day 2. Group 5 (orange) involves sunitinib being given once daily for 12 days, with a single dose of irinotecan at day 15.

Figure 6

Experiment 3. Minimal tumor diameter achieved (y‐axis) in mice treated with sunitinib 40 mg/kg daily for 12 days in combination with irinotecan 90 mg/kg (unique 5‐minute intravenous infusion) given at different time (x‐axis) in the evaluation experiment (Supplemental Table S4). Error bars represent one standard deviation of experimental data, while continuous line represents the model prediction.