Table 8.
Evaluation of transporter inhibition potential for canagliflozin using basic approaches
| Transporter and location | In vitro Inhibition | FDAb | EMAc | ||
|---|---|---|---|---|---|
| Intestinal | Ki a | I d /Ki < 10 | Interaction warranted | R = 0.1x I d | Interaction warranted |
| Pgp | 9.65 | 125.6 | Yes | 268 | Yes |
| MRP2 | 10.76 | 139.5 | Yes | 268 | Yes |
| Hepatic | Ki a | 1 + ([I uinlet,max ) < 1.25 | R = 25x [I u, inlet max ] | ||
| OATP1B3 | >50 | 1.174 | No | 4.35 | No |
| Renal | Ki a | I u, /IC50 < 0.1 | R = 50x [I u, ] | ||
| OCT2 | >50 | 0.0011 | No | 5.5 | No |
| Pgp | 9.65 | 0.0057 | No | 5.5 | No |
[I] represents mean steady‐state total Cmax in plasma following once daily administration of highest clinical dose 300 mg (10.5 μmol l–1)
[Iu] represents unbound mean steady‐state Cmax in plasma following once daily administration of highest clinical dose 300 mg (0.11 μmol l–1)
a
Ki = IC50/2, assumption of competitive inhibition
Id = Dose of canagliflozin/250 ml
Iu, inlet max =0.174 μmol l–1, unbound hepatic inlet concentration after oral administration at 300 mg canagliflozin
b
If R < the given factor, no in vivo DDI study is needed.
c
If Ki > R, interaction potential is excluded