Summary of fostamatinib (100 mg) dose-related concentration and inhibitory kinetic parameters for calculation of [I]/Ki ratios and R-value
R-value is equal to (1 + [Iinlet max u]/Ki).
| Transporter | I1 | I2 | IC50 | [I1]/Ki | [I2]/Ki | Iinlet max u | R-Value | Potential for DDI ([I1]/Ki ≥ 0.1, [I2]/Ki ≥ 10, R-value ≥ 1.25) |
|---|---|---|---|---|---|---|---|---|
| μM | μM | μM | μM | |||||
| BCRP | 1.6a | 691 | 0.050b | 32 | 13,820 | NA | NA | Yes (intestinal) |
| 0.031c | 52 | NA | ||||||
| OATP1B1 | 1.6a | NA | > 10 | 0.16 | NA | 0.284 | 1.03 | No |
I1, mean steady-state maximum plasma concentration (Cmax) value for total systemic drug (R406); I2, maximal theoretical gastrointestinal concentration of R788 prodrug [calculated from dose (mol)/250 ml]; Iinlet max u, maximum unbound liver inlet concentration, calculated as fu × [(I1) + (Fa × ka × dose/Qh)], where fu is the fraction unbound (R406 = 0.018), Fa is the fraction absorbed (as default taken to be 1.0), ka is the absorption rate constant (as default taken to be 0.1 min−1), and Qh is hepatic blood flow (1500 ml/min); Ki, absolute inhibition constant (equates to IC50 in these assays as probe substrate concentration used is < <<< Km); NA, not applicable.
↵a Derived from plasma concentration data determined from multiple clinical studies.
↵b Fostamatinib (R788).
↵c R406.