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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

1
Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
College of Pharmacy, Washington State University, Spokane, Washington, USA.
3
Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
4
School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
6
ProPharma Services, LLC, Oxford, Connecticut, USA.

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

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