ColdDDI: Evaluating Knowledge Utilization in Cold-Start Drug-Drug Interaction Prediction

Jiheng Liang, Chen Zhao, Di Wu, Chenyang Bu, Yunpeng Hong +2

Cold-start drug-drug interaction (DDI) prediction tests whether models can identify clinically significant interactions for drugs without training-time interaction history. Existing benchmarks mostly report aggregate edge-prediction scores, leaving a key evaluation question unanswered: when models receive molecular, textual, or knowledge-graph (KG) evidence, do they actually use the evidence that pharmacologically supports the interaction? We introduce ColdDDI, a reconstructible diagnostic benchmark built from DrugBank 5.1.13, with 1,900 approved small-molecule drugs and 565,731 positive DDI pairs. ColdDDI evaluates pairs with zero, one, or two unseen drugs. It also annotates each interaction by whether it changes drug exposure or drug effect, and by whether the biomedical knowledge graph contains shared enzymes, transporters, or targets that can plausibly mediate the interaction. These annotations separate evidence availability from predictive dependence. We evaluate eight conventional DDI methods and 13 LLMs; for open-weight LLMs, we test five prompt patterns and use masking, drug replacement, and channel-sensitivity metrics to probe knowledge utilization. ColdDDI exposes that,…