Send to

Choose Destination
CPT Pharmacometrics Syst Pharmacol. 2014 Mar 26;3:e107. doi: 10.1038/psp.2013.69.

Physiologically based pharmacokinetic modeling framework for quantitative prediction of an herb-drug interaction.

Author information

Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
College of Pharmacy, Washington State University, Spokane, Washington, USA.
Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
ProPharma Services, LLC, Oxford, Connecticut, USA.


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.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e107; doi:10.1038/psp.2013.69; advance online publication 26 March 2014.

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center