Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Tyler Graf, Research Scientist (Creator)
Nicholas Oberlies, Patricia A. Sullivan Distinguished Professor of Chemistry (Creator)
The University of North Carolina at Greensboro (UNCG )
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Abstract: 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.

Additional Information

CPT: Pharmacometrics & Systems Pharmacology, 3, e107
Language: English
Date: 2014
Biochemistry, pharmacokinetics, Herb-drug interactions

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