Herb–drug interaction predictions remain challenging. Physiologically based
pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential
herb–drug interactions using the semipurified milk thistle preparation, silibinin,
as an exemplar herbal product. Interactions between silibinin constituents and the probe
substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose
(160 mg/day × 14 days) was predicted to increase midazolam area under the
curve (AUC) by 1%, which was corroborated with external data; a higher dose
(1,650 mg/day × 7 days) was predicted to increase midazolam and
(S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study
confirmed minimal interaction between high-dose silibinin and both midazolam and
(S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly,
(R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically
important. Application of this PBPK modeling framework to other herb–drug
interactions could facilitate development of guidelines for quantitative prediction of
clinically relevant interactions.
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 (AUC0‐inf) and maximal concentration (Cmax). Model‐informed clinical evaluation of the silibinin–raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0‐inf and Cmax 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.
New drugs were not required to undergo premarket safety testing in the United States until 1938, when a therapeutic disaster-the Elixir Sulfanilamide tragedy-prompted Congress to pass a bill mandating this now-routine process. History repeated itself nearly 25 years later, when another therapeutic disaster-the thalidomide tragedy-led to passage of new amendments in 1962 to ensure drug efficacy and greater drug safety. As is typical with historical events, critical information was gained that led to novel approaches for understanding, predicting, diagnosing, and managing drug-induced toxicities. Continued refinement of current, along with development of new, approaches will mitigate future drug-related catastrophes, with the goal of avoiding them entirely.
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