title: Physiologically based pharmacokinetic modeling framework for quantitative prediction of an herb-drug interaction.
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.
authors.affiliation: Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Brantley
authors.affiliation: College of Pharmacy, Washington State University, Spokane, Washington, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Gufford
authors.affiliation: Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dua
authors.affiliation: Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Fediuk
authors.affiliation: Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Graf
authors.affiliation: School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Y V
authors.initials: YV
authors.lastname: Scarlett
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Frederick
authors.affiliation: ProPharma Services, LLC, Oxford, Connecticut, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Fisher
authors.affiliation: Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Oberlies
authors.affiliation: College of Pharmacy, Washington State University, Spokane, Washington, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Paine