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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.


Effects of silibinin (1,650 mg/day for 7 days) on (a,c,e)Cmax and (b,d,f) AUC of (a,b)(R)-warfarin, (c,d) (S)-warfarin, and(e,f) midazolam in 12 healthy volunteers following oral administrationof warfarin (10 mg) and midazolam (5 mg). Open symbols connected by solidlines denote individual values. Solid symbols connected by dashed lines denote geometricmeans.
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fig3: Effects of silibinin (1,650 mg/day for 7 days) on (a,c,e)Cmax and (b,d,f) AUC of (a,b)(R)-warfarin, (c,d) (S)-warfarin, and(e,f) midazolam in 12 healthy volunteers following oral administrationof warfarin (10 mg) and midazolam (5 mg). Open symbols connected by solidlines denote individual values. Solid symbols connected by dashed lines denote geometricmeans.

Mentions: Warfarin enantiomers were absorbed rapidly during both study phases, with mediantmax occurring at 1.25 and 1.5 hours for (R)- and(S)-warfarin, respectively (Figure 2a).Coadministration with silibinin did not alter median (S)-warfarintmax but delayed median (R)-warfarintmax by 15 minutes. Relative to control (baseline), silibinindecreased (R)-warfarin geometric mean Cmax by 17%(Figure 3a; Table2) and AUC0–48 by 15% (Figure3b; Table 2). Silibinindecreased geometric mean (S)-warfarin Cmax by 2%(Figure 3c; Table2). Geometric mean AUC0–48 of (S)-warfarinincreased by 13% (Figure 3d; Table 2), with three subjects lying outside the predefinedno effect range (0.75–1.33). The 90% confidence intervals for the(S)-warfarin primary endpoints (Cmax and AUC) lay withinthe predefined no effect range (Table 2).


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)

Effects of silibinin (1,650 mg/day for 7 days) on (a,c,e)Cmax and (b,d,f) AUC of (a,b)(R)-warfarin, (c,d) (S)-warfarin, and(e,f) midazolam in 12 healthy volunteers following oral administrationof warfarin (10 mg) and midazolam (5 mg). Open symbols connected by solidlines denote individual values. Solid symbols connected by dashed lines denote geometricmeans.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Effects of silibinin (1,650 mg/day for 7 days) on (a,c,e)Cmax and (b,d,f) AUC of (a,b)(R)-warfarin, (c,d) (S)-warfarin, and(e,f) midazolam in 12 healthy volunteers following oral administrationof warfarin (10 mg) and midazolam (5 mg). Open symbols connected by solidlines denote individual values. Solid symbols connected by dashed lines denote geometricmeans.
Mentions: Warfarin enantiomers were absorbed rapidly during both study phases, with mediantmax occurring at 1.25 and 1.5 hours for (R)- and(S)-warfarin, respectively (Figure 2a).Coadministration with silibinin did not alter median (S)-warfarintmax but delayed median (R)-warfarintmax by 15 minutes. Relative to control (baseline), silibinindecreased (R)-warfarin geometric mean Cmax by 17%(Figure 3a; Table2) and AUC0–48 by 15% (Figure3b; Table 2). Silibinindecreased geometric mean (S)-warfarin Cmax by 2%(Figure 3c; Table2). Geometric mean AUC0–48 of (S)-warfarinincreased by 13% (Figure 3d; Table 2), with three subjects lying outside the predefinedno effect range (0.75–1.33). The 90% confidence intervals for the(S)-warfarin primary endpoints (Cmax and AUC) lay withinthe predefined no effect range (Table 2).

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.