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Quantitative prediction and clinical evaluation of an unexplored herb-drug interaction mechanism in healthy volunteers.

Gufford BT, Barr JT, González-Pérez V, Layton ME, White JR, Oberlies NH, Paine MF - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation.Model-informed clinical evaluation of the silibinin-raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0-inf and Cmax ratios lying within the predefined no effect range (0.75-1.33).Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb-drug combinations.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy Washington State University Spokane, Washington USA.

ABSTRACT
Quantitative prediction of herb-drug interaction risk remains challenging. A quantitative framework to assess a potential interaction was used to evaluate a mechanism not previously tested in humans. The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation. Physiologically based pharmacokinetic (PBPK) model simulations of the silibinin-raloxifene interaction predicted up to 30% increases in raloxifene area under the curve (AUC0-inf) and maximal concentration (Cmax). Model-informed clinical evaluation of the silibinin-raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0-inf and Cmax ratios lying within the predefined no effect range (0.75-1.33). Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb-drug combinations. This quantitative framework can be used to develop guidances to evaluate potential herb-drug interactions prospectively, providing evidenced-based information about the risk or safety of these interactions.

No MeSH data available.


Geometric mean concentration–time profiles of silybin A (gray circles) and silybin B (crimson triangles) following oral administration of silibinin (480 mg three times daily × 4 days). Solid lines denote PBPK model simulations of mean concentration–time profiles using Berkeley Madonna (a) or SimCYP (b). Dashed lines denote upper and lower 90% confidence intervals (b). Symbols and error bars denote observed geometric means and upper limits of the 90% confidence interval, respectively.
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psp412047-fig-0004: Geometric mean concentration–time profiles of silybin A (gray circles) and silybin B (crimson triangles) following oral administration of silibinin (480 mg three times daily × 4 days). Solid lines denote PBPK model simulations of mean concentration–time profiles using Berkeley Madonna (a) or SimCYP (b). Dashed lines denote upper and lower 90% confidence intervals (b). Symbols and error bars denote observed geometric means and upper limits of the 90% confidence interval, respectively.

Mentions: Simulations conducted using Berkeley Madonna predicted an ∼30% increase in raloxifene AUC0‐inf and Cmax with minimal change (3%) in t1/2. The SimCYP model predicted negligible changes in raloxifene pharmacokinetic outcomes (≤5%) (Table3). Both models predicted similar overall exposure to silybin A and silybin B (Table3, Figure4). The SimCYP model predicted rapid silibinin elimination (t1/2 <3 hours). The Berkeley Madonna model predicted longer half‐lives for silybin A and silybin B, consistent with previous clinical study outcomes when silibinin was administered at the same dose for 7 days.2 Maximum silibinin (silybin A + silybin B) intestinal tissue concentrations predicted by the SimCYP model (∼26 µM) were lower than those predicted by the Berkeley Madonna Model (∼61 µM). Both estimates were within reported intestinal tissue concentrations (20–310 µM).38


Quantitative prediction and clinical evaluation of an unexplored herb-drug interaction mechanism in healthy volunteers.

Gufford BT, Barr JT, González-Pérez V, Layton ME, White JR, Oberlies NH, Paine MF - CPT Pharmacometrics Syst Pharmacol (2015)

Geometric mean concentration–time profiles of silybin A (gray circles) and silybin B (crimson triangles) following oral administration of silibinin (480 mg three times daily × 4 days). Solid lines denote PBPK model simulations of mean concentration–time profiles using Berkeley Madonna (a) or SimCYP (b). Dashed lines denote upper and lower 90% confidence intervals (b). Symbols and error bars denote observed geometric means and upper limits of the 90% confidence interval, respectively.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759704&req=5

psp412047-fig-0004: Geometric mean concentration–time profiles of silybin A (gray circles) and silybin B (crimson triangles) following oral administration of silibinin (480 mg three times daily × 4 days). Solid lines denote PBPK model simulations of mean concentration–time profiles using Berkeley Madonna (a) or SimCYP (b). Dashed lines denote upper and lower 90% confidence intervals (b). Symbols and error bars denote observed geometric means and upper limits of the 90% confidence interval, respectively.
Mentions: Simulations conducted using Berkeley Madonna predicted an ∼30% increase in raloxifene AUC0‐inf and Cmax with minimal change (3%) in t1/2. The SimCYP model predicted negligible changes in raloxifene pharmacokinetic outcomes (≤5%) (Table3). Both models predicted similar overall exposure to silybin A and silybin B (Table3, Figure4). The SimCYP model predicted rapid silibinin elimination (t1/2 <3 hours). The Berkeley Madonna model predicted longer half‐lives for silybin A and silybin B, consistent with previous clinical study outcomes when silibinin was administered at the same dose for 7 days.2 Maximum silibinin (silybin A + silybin B) intestinal tissue concentrations predicted by the SimCYP model (∼26 µM) were lower than those predicted by the Berkeley Madonna Model (∼61 µM). Both estimates were within reported intestinal tissue concentrations (20–310 µM).38

Bottom Line: The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation.Model-informed clinical evaluation of the silibinin-raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0-inf and Cmax ratios lying within the predefined no effect range (0.75-1.33).Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb-drug combinations.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy Washington State University Spokane, Washington USA.

ABSTRACT
Quantitative prediction of herb-drug interaction risk remains challenging. A quantitative framework to assess a potential interaction was used to evaluate a mechanism not previously tested in humans. The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation. Physiologically based pharmacokinetic (PBPK) model simulations of the silibinin-raloxifene interaction predicted up to 30% increases in raloxifene area under the curve (AUC0-inf) and maximal concentration (Cmax). Model-informed clinical evaluation of the silibinin-raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0-inf and Cmax ratios lying within the predefined no effect range (0.75-1.33). Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb-drug combinations. This quantitative framework can be used to develop guidances to evaluate potential herb-drug interactions prospectively, providing evidenced-based information about the risk or safety of these interactions.

No MeSH data available.