Abstract 4761: Understanding three-drug combinations: optimizing scheduling while avoiding toxicity
Authors: Stoddard Madison , Yuan Lin , Van Egeren Debra , Chen Andrew , Bottino Dean , Chakravarty Arijit 
Published: March 2024

Abstract
The promise of combination therapies in managing tumor resistance is constrained by the therapeutic window (the difference between efficacious and toxic doses). We have sought to understand the impact of dose scheduling on the emergence of resistance, using a mathematical model-based approach linking pharmacokinetics (PK) to a parsimonious evolutionary model of tumor growth incorporating the emergence of drug resistance. Here, we analyze the potential of a three-drug combination to minimize toxicity while preventing the emergence of resistance. We simulated eight tumor subpopulations representing resistance to one, two or three hypothetical drugs, using an exponential growth model with growth penalties based on drug concentrations. We used the model to simulate the effects of pairs of antagonistic, synergistic, and additive drugs on the growth of sensitive and resistant populations in a tumor. Final tumor volume and resistant population were used to compare the efficacy of various drug schedules. We assumed an overlapping neutropenia-like toxicity as the dose-limiting toxicity for the three drug combination, which we have previously shown to be proportional to the peak moving average drug concentration over 18 days. Final tumor volume and peak toxicity were used to compare the effectiveness of various dosing strategies and interaction combinations. Synchronous dosing results in the greatest drug interaction effect between any two drugs. When all interactions between the three drugs are either antagonistic or synergistic, the greatest effect is observed when all drugs are dosed simultaneously. The drugs are most toxic when all three are dosed simultaneously or nearly simultaneously. Our work shows that time sensitivity—that is, the magnitude of the changes in efficacy associated with small changes in schedule—varies with phase offset. Scheduling is most time sensitive when all drugs are dosed simultaneously or nearly simultaneously; dosing of two drugs simultaneously is less time sensitive. Three-drug combinations are an effective means of preventing complete resistance. While simultaneous dosing of two or more drugs confers the greatest efficacy, such simultaneous dosing results in greater peak toxicity because of higher simultaneous drug concentrations. A potential compromise is the simultaneous dosing of two of the three drugs, which results in an intermediate toxicity. Dosing of two drugs simultaneously is also less time sensitive, advantageous in a practical sense as it is more robust to patient dosing error. While the approach used here is based on hypothetical drug properties, it provides a framework that is readily applicable to real-world drug combinations, with the potential for practical insights to guide the framing of the Target Product Profile for three-drug combinations.
Citation Format: Madison Stoddard, Lin Yuan, Debra Van Egeren, Andrew Chen, Dean Bottino, Arijit Chakravarty. Understanding three-drug combinations: optimizing scheduling while avoiding toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4761.