 Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as either synergistic or antagonistic, depending on whether the observed combination response deviates from the expected effect calculated based on a reference model of non-interaction. Existing reference models were developed for low-throughput drug combination experiments, making them incompatible with the complex drug interactions observed in large-scale dose response matrix experiments. To address this limitation, we proposed a new reference model called zero-interaction potency, ZIP. This model captures the drug interaction relationships by comparing the change in potency of the dose response curve between individual drugs and their combinations. We used a delta score to measure the deviation from the expectation of no interaction and proved that a delta score of zero indicates both probabilistic independence and dose additivity. We then applied this model to a large-scale anti-cancer drug combination experiment, demonstrating its ability to capture the experimentally confirmed drug synergy while maintaining a low false positive rate. Additionally, we proposed using an interaction landscape over the entire dose response matrix to identify and quantify synarch. This article was authored by Bug von Yadav, Krzysztof Wennerberg, Taro Adokalio, and others. We are article.tv, links in the description below.