A Rule-Based Inference Framework to Explore and Explain the Biological Related Mechanisms of Potential Drug-Drug Interactions

As more drugs are developed and the incidence of polypharmacy increases, it is becoming critically important to anticipate potential DDIs before they occur in the clinic, along with those for which effects might go unobserved. However, traditional methods for DDI identification are unable to coalesce interaction mechanisms out of vast lists of potential or known DDIs, much less study them accurately. Computational methods have great promise but have realized only limited clinical utility. This work develops a rule-based inference framework to predict DDI mechanisms and support determination of their clinical relevance. Given a drug pair, our framework interrogates and describes DDI mechanisms based on a knowledge graph that integrates extensive available biomedical resources through semantic web technologies and backward chaining inference, effectively identifying facts within the graph that prove and explain the mechanisms of the drugs' interaction. The framework was evaluated through a case study combining a chemotherapy agent, irinotecan, and a widely used antibiotic, levofloxacin. The mutual interactions identified indicate that our framework can effectively explore and explain the mechanisms of potential DDIs. This approach has the potential to improve drug discovery and design and to support rapid and cost-effective identification of DDIs along with their putative mechanisms, a key step in determining clinical relevance and supporting clinical decision-making.