DDI risk due to transporter inhibition by dabrafenib and metabolites
| R Threshold | Dabrafenib | Hydroxy-Dabrafenib | Carboxy-Dabrafenib | Desmethyl-Dabrafenib | Total R Value | Total R = 1+Σ(Ri-1) | ||
|---|---|---|---|---|---|---|---|---|
| R value | R value | R value | R value | |||||
| BCRP intestinal | EMA | 11 | 2.3 | 2.310 | R = 1+I/IC50; I = soluble dose | |||
| FDA | 11 | 116.5 | 116.5* | R = 1+I/IC50; I = dose in 250 ml | ||||
| BCRP hepatic/renal | EMA | 1.02 | 1.003 | 1.001 | 1.001 | 1.0013 | 1.006 | R = 1+I/IC50; I = Cmax,p,u |
| FDA | 1.1 | 1.284 | 1.023 | 1.056 | 1.1270 | 1.490* | R=1+I/IC50; I = Cmax,p | |
| OATP1B1 | EMA | 1.04 | 1.084 | 1.016 | 1.006 | 1.0083 | 1.114* | R = 1+I/IC50; I = Iu,inlet,max,b for dabrafenib, I = Cmax,p,u for metabolites |
| FDA | 1.25 | 1.084 | 1.016 | 1.006 | 1.0083 | 1.114 | R = 1+I/IC50; I = Iu,inlet,max,b for dabrafenib, I = Cmax,p,u for metabolites | |
| OATP1B3 | EMA | 1.04 | 1.025 | 1.003 | 1.006 | 1.0016 | 1.036 | R = 1+I/IC50; I = Iu,inlet,max,b for dabrafenib, I = Cmax,p,u for metabolites |
| FDA | 1.25 | 1.025 | 1.003 | 1.006 | 1.0016 | 1.036 | R = 1+I/IC50; I = Iu,inlet,max,b for dabrafenib, I = Cmax,p,u for metabolites | |
| OAT1 | EMA | 1.02 | 1.004 | 1.002 | 1.004 | 1.0007 | 1.011 | R = 1+I/IC50; I = Cmax,p,u |
| FDA | 1.1 | 1.004 | 1.002 | 1.004 | 1.0007 | 1.011 | R = 1+I/IC50; I = Cmax,p,u | |
| OAT3 | EMA | 1.02 | 1.008 | 1.010 | 1.012 | 1.0020 | 1.032* | R = 1+I/IC50; I = Cmax,p,u |
| FDA | 1.1 | 1.008 | 1.010 | 1.012 | 1.0020 | 1.032 | R = 1+I/IC50; I = Cmax,p,u | |
| OCT2 | EMA | 1.02 | 1.003 | 1.0002 | 1.003 | R = 1+I/IC50; I = Cmax,p,u | ||
| FDA | 1.1 | 1.003 | 1.0002 | 1.003 | R = 1+I/IC50; I = Cmax,p,u |
Parameter values used to calculate R values are shown in Supplemental Table 1.
↵*: R threshold has been exceeded