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

Brantley SJ, Gufford BT, Dua R, Fediuk DJ, Graf TN, Scarlett YV, Frederick KS, Fisher MB, Oberlies NH, Paine MF - CPT Pharmacometrics Syst Pharmacol (2014)

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

View Article: PubMed Central - PubMed

Affiliation: Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 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.

No MeSH data available.


Mean concentration–time profile (0–6 hours) of midazolam in 19 healthyvolunteers following an 8 mg oral midazolam dose given alone (open symbols) orfollowing a 14-day treatment with milk thistle product (solid symbols).18 Lines denote physiologically based pharmacokineticmodel simulations of the midazolam concentration–time profile when given alone(black) or with milk thistle (green). The dotted green line denotes incorporation ofreversible inhibition of CYP3A, whereas the dashed green line denotes incorporation ofmechanism-based inhibition of CYP3A. Symbols and error bars denote observed means andSDs, respectively, and were obtained from ref. 18.
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fig1: Mean concentration–time profile (0–6 hours) of midazolam in 19 healthyvolunteers following an 8 mg oral midazolam dose given alone (open symbols) orfollowing a 14-day treatment with milk thistle product (solid symbols).18 Lines denote physiologically based pharmacokineticmodel simulations of the midazolam concentration–time profile when given alone(black) or with milk thistle (green). The dotted green line denotes incorporation ofreversible inhibition of CYP3A, whereas the dashed green line denotes incorporation ofmechanism-based inhibition of CYP3A. Symbols and error bars denote observed means andSDs, respectively, and were obtained from ref. 18.

Mentions: Prediction of silibinin–drug interaction magnitude. Simulations of apreviously reported milk thistle-midazolam interaction, assuming reversible CYP3Ainhibition solely due to silybin A and silybin B, demonstrated negligible changes in themidazolam concentration–time profile (Figure1). The milk thistle product tested, silymarin, contained 100 mg ofsilybin A and 180 mg of silybin B and was administered daily for 14days.18 Simulations assumingmechanism-based CYP3A inhibition predicted a 30% and 60% increase in midazolamCmax and AUC, respectively; increases of 6% and 3% inmidazolam Cmax and AUC, respectively, were reported18 (Figure 1).


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

Brantley SJ, Gufford BT, Dua R, Fediuk DJ, Graf TN, Scarlett YV, Frederick KS, Fisher MB, Oberlies NH, Paine MF - CPT Pharmacometrics Syst Pharmacol (2014)

Mean concentration–time profile (0–6 hours) of midazolam in 19 healthyvolunteers following an 8 mg oral midazolam dose given alone (open symbols) orfollowing a 14-day treatment with milk thistle product (solid symbols).18 Lines denote physiologically based pharmacokineticmodel simulations of the midazolam concentration–time profile when given alone(black) or with milk thistle (green). The dotted green line denotes incorporation ofreversible inhibition of CYP3A, whereas the dashed green line denotes incorporation ofmechanism-based inhibition of CYP3A. Symbols and error bars denote observed means andSDs, respectively, and were obtained from ref. 18.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042458&req=5

fig1: Mean concentration–time profile (0–6 hours) of midazolam in 19 healthyvolunteers following an 8 mg oral midazolam dose given alone (open symbols) orfollowing a 14-day treatment with milk thistle product (solid symbols).18 Lines denote physiologically based pharmacokineticmodel simulations of the midazolam concentration–time profile when given alone(black) or with milk thistle (green). The dotted green line denotes incorporation ofreversible inhibition of CYP3A, whereas the dashed green line denotes incorporation ofmechanism-based inhibition of CYP3A. Symbols and error bars denote observed means andSDs, respectively, and were obtained from ref. 18.
Mentions: Prediction of silibinin–drug interaction magnitude. Simulations of apreviously reported milk thistle-midazolam interaction, assuming reversible CYP3Ainhibition solely due to silybin A and silybin B, demonstrated negligible changes in themidazolam concentration–time profile (Figure1). The milk thistle product tested, silymarin, contained 100 mg ofsilybin A and 180 mg of silybin B and was administered daily for 14days.18 Simulations assumingmechanism-based CYP3A inhibition predicted a 30% and 60% increase in midazolamCmax and AUC, respectively; increases of 6% and 3% inmidazolam Cmax and AUC, respectively, were reported18 (Figure 1).

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

View Article: PubMed Central - PubMed

Affiliation: Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 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.

No MeSH data available.