Gufford B T, Barr J T, González-Pérez V, Layton M E, White J R, Oberlies N H, Paine M F
College of Pharmacy Washington State University Spokane, Washington USA.
College of Medical Sciences Washington State University Spokane, Washington USA.
CPT Pharmacometrics Syst Pharmacol. 2015 Dec;4(12):701-10. doi: 10.1002/psp4.12047. Epub 2015 Nov 28.
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.
草药与药物相互作用风险的定量预测仍然具有挑战性。一个用于评估潜在相互作用的定量框架被用来评估一种此前未在人体中测试过的机制。半纯化的水飞蓟产品水飞蓟宾被选为雷洛昔芬肠道葡萄糖醛酸化的典型草药产品抑制剂。水飞蓟宾与雷洛昔芬相互作用的基于生理的药代动力学（PBPK）模型模拟预测，雷洛昔芬曲线下面积（AUC0-inf）和最大浓度（Cmax）最多可增加30%。对水飞蓟宾与雷洛昔芬相互作用的模型指导临床评估表明，临床相互作用可能性极小，观察到的雷洛昔芬AUC0-inf和Cmax几何平均比值处于预先定义的无效应范围内（0.75 - 1.33）。进一步完善PBPK建模和模拟方法将增强预测的可信度，并促进其对其他草药 - 药物组合的通用性。这个定量框架可用于制定前瞻性评估潜在草药 - 药物相互作用的指南，提供有关这些相互作用风险或安全性的循证信息。
