Abstract 4520: Biological coupling: Drug synergy, cross-resistance, and schedule effects in combination therapy
Authors: Chen Andrew , Zopf Christopher J. , Wu Jing-Tao , Shyu Wen Chyi , Chakravarty Arijit 
Published: August 2015

Abstract
Introduction
Combination therapy promises to enhance and extend benefit to oncology patients, but development of drug combinations engenders challenges beyond those of single agents. In this work, we use theoretical models of combination efficacy to demonstrate a potential link between drug interactions, cross-resistance, and dosing schedule effects.
Methods
First, we investigated the relationship between efficacy interaction and schedule effects by building a dynamic pharmacokinetic (PK)/efficacy (E) model to generate theoretical tumor volume trajectories in response to exposure to two drugs. We used a single compartment PK model to simulate the plasma exposure to each drug following various dosing schedules, and exponential tumor growth was inhibited by a drug effect model consisting of the sum of single agent effects and their product with an interaction coefficient. Simulations of this PK/E model for 1000 pairs of drugs with randomized properties and interaction strengths were compared for dosing schedules with high or low concomitance, respectively. Next, we used a Moran simulation to study the effect of interaction strength on sensitivity loss in a heterogeneous population. For a tumor initially comprising 1000 subclones (either doubly sensitive, singly resistant to either drug, or doubly resistant), we simulate based on relative subclone fitnesses the time steps until fixation of a resistant population. We then apply the PK/E model assuming a multi-clone tumor to elucidate the relationship between synergy, dosing schedule, and the rise of cross-resistance by comparing response to in-phase and off-phase combination dosing and across a range of interaction strengths.
Results
Simulation of the PK/E model demonstrates that tumor growth inhibition of in-phase and off-phase dosing schedules diverges in a linear relationship with the interaction strength. Moran simulations show synergistic compounds are more likely to lead to fixation of a doubly resistant subclone within a population of tumor cells, and that it will happen faster than with nonsynergistic combinations. Comparing the tumor volume and sensitive fraction trajectories in response to either in-phase or off-phase dosing of a synergistic combination revealed prolonged sensitivity and reduced tumor load when dosing out of phase to avoid the synergistic interaction. Sweeping the interaction strength shows a minimum in long-term tumor growth rate when the combination exerts its effect additively.
Conclusions
While synergistic drug combinations may provide increased efficacy beyond additive effects of the drugs, this theoretical framework predicts that positive interactions will lead to scheduling challenges and faster resistance emergence. Counter-intuitively, it suggests the best strategy for long-term patient benefit is to use drugs with additive efficacy or non-concomitant dosing to avoid synergistic interactions.
Citation Format: Andrew Chen, Christopher J. Zopf, Jing-Tao Wu, Wen Chyi Shyu, Arijit Chakravarty. Biological coupling: Drug synergy, cross-resistance, and schedule effects in combination therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4520. doi:10.1158/1538-7445.AM2015-4520