Quantitative prediction and clinical evaluation of an unexplored herb–drug interaction mechanism in healthy volunteers

Quantitative prediction of herb–drug interaction risk remains challenging. A quantitative framework to assess a potential interaction was used to evaluate a mechanism not previously tested in humans. The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation. Physiologically based pharmacokinetic (PBPK) model simulations of the silibinin–raloxifene interaction predicted up to 30% increases in raloxifene area under the curve (AUC(0‐inf)) and maximal concentration (C(max)). Model‐informed clinical evaluation of the silibinin–raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC(0‐inf) and C(max) ratios lying within the predefined no effect range (0.75–1.33). Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb–drug combinations. This quantitative framework can be used to develop guidances to evaluate potential herb–drug interactions prospectively, providing evidenced‐based information about the risk or safety of these interactions.