Parameter inputs and assumptions used in perpetrator mechanistic static mathematical model predictions of dabrafenib DDI
| Parameter Input | Values | Definition of Inputs | ||
|---|---|---|---|---|
| Dabrafenib | Hydroxy-Dabrafenib | Desmethyl-Dabrafenib | ||
| Cmaxssa (μM) | 2.8 | 1.9 | 0.69 | |
| Protein Bindingb | 99.7 | 96.3 | 99.9 | |
| Liver:Plasma Ratioc | 15: 1 | 16.5: 1 | 16.8: 1 | |
| Dose | 150 mg (twice daily) | |||
| ka | 0.03 min-1d | Rate of inhibitor absorption | ||
| Fa | 1 | Fraction of inhibitor absorbed in blood | ||
| Qh | 1,617 ml/mine | Liver blood flow | ||
| Fa | 1 | Fraction of inhibitor absorbed into the enterocyte | ||
| Fg | 0.57h | |||
| Qg | 300 ml/mine | Enterocytic blood flow | ||
| Kdeg,h | 0.000413 kdeg.minf | Degradation rate of the hepatic enzyme | ||
| Kdeg,g | 0.000561 kdeg/ming | Degradation rate of the intestinal enzyme | ||
| Indmax (Ψ) | 26.9 | |||
| IndC50 | 1.6 μM | |||
↵a Steady-state Cmax values obtained from (Ouellet et. al., 2013).
↵b Protein binding data measured separately.
↵c Liver:plasma ratio determined from QWBA measured separately.
↵d Obach et al., 2006.
↵e U.S. Food and Drug Administration, 2012.
↵f Quinney et al., 2010.
↵g Yang et al., 2008.
↵h Borges et al., 2005.