Drug-Drug Interaction Risk Assessment Strategies for Biologics in Inflammatory Bowel Disease: A Literature-Based...

Biologic therapies are traditionally regarded as having low potential for drug-drug interactions (DDIs) due to their large molecular size and limited direct involvement with drug-metabolizing enzymes and transporters (DMETs). However, accumulating evidence indicates that these drug products may indirectly modulate DMET activity through cytokine-mediated mechanisms, particularly in the context of inflammatory diseases. Pro-inflammatory cytokines such as interleukin-6 have been shown to suppress the expression of cytochrome P450 (CYP) enzymes in vitro, most notably CYP3A4, thereby potentially altering the metabolic clearance of concomitant medications. This phenomenon may be pertinent in conditions such as inflammatory bowel disease (IBD) where chronic inflammation and systemic physiological alterations may significantly influence drug disposition. Although the U.S. Food and Drug Administration provides a decision framework to assess large molecule DDI risk based on the mechanism of action, it does not offer a standardized, mechanistic approach for evaluating such interactions. In response, alternative methodologies such as the use of endogenous biomarkers like 4β-hydroxycholesterol, a proposed surrogate for CYP3A activity, and pharmacokinetic modeling are in exploration to support DDI risk assessment to potentially avoid dedicated clinical trials in patients. This review evaluates current knowledge on biologics-mediated DDIs with a particular focus on drug-disease interactions in IBD. There is an opportunity for a more structured, mechanistically informed evaluation that integrates cytokine profiling and biomarker-based approaches to identify DDI risk and enhance the overall understanding of the degree of interaction and its clinical significance.