TABLE 1.
Ibrutinib and PCI-45227 pharmacokinetic parameters.
| Mouse genotype | Ibrutinib dose (mg/kg) | Cotreatment (dose mg/kg) | Ibrutinib Cmax (ng/mL) | Ibrutinib AUC(0-last) (ng/h/mL) | F (%) | Ibrutinib AUC fold increase | PCI-45227 Cmax (ng/mL) | PCI-45227 AUC(0-last) (ng/h/mL) | PCI-45227: Ibrutinib AUC ratio |
|---|---|---|---|---|---|---|---|---|---|
| Wild-type FVB | 10 | PEG400 | 663 (328) | 768 (147) | NC | — | 246 (54) | 668 (155) | 0.87 |
| Wild-type FVB | 10 | Ketoconazole (50) | 3,105 (404)a | 8,315 (1,543)a | NC | 10.8 | 288 (89) | 682 (250) | 0.08 |
| Wild-type FVB | 10 | Corn oil | 292 (79) | 284 (41) | 5.5 | — | 219 (61)b | 563 (91)d | 2.0 |
| Wild-type FVB | 10 | Cobicistat (30) | 1,438 (567) | 2,599 (471)c | 50 | 9.2 | 45 (14)c | 139 (56)c | 0.05 |
| Wild-type FVB | 10 | Corn oile | 394 (72) | 459 (59) | 8.8 | — | 405 (74) | 917 (128) | 2.0 |
| Wild-type FVB | 10 | Cobicistate (30) | 925 (220) | 2,254 (335)c | 43 | 4.9 | 211 (65) | 560 (73)b | 0.25 |
| Wild-type FVB | 10 | None | 430 (63) | 301 (38) | 5.8 | — | 447 (45) | 765 (79) | 2.5 |
| CYP3A−/− | 10 | None | 1,762 (229) | 2,347 (203)c | 45 | 7.8 | 8.2 (2.1)c | 6.3 (1.7)c | 0.003 |
| CYP3A−/− | 10 | Corn oil | 1,389 (698) | 1,410 (260) | 27 | — | ND | ND | ND |
| CYP3A−/− | 10 | Cobicistat (30) | 845 (230) | 1,660 (131)d | 32 | 1.2 | ND | ND | ND |
| Wild-type FVB | 30 | None | 554 (107) | 1,713 (163) | 11 | — | 837 (77) | 3,281 (154) | 1.9 |
| Wild-type FVB | 4 | Cobicistat (30) | 589 (105) | 1,202 (142)b | 58 | 0.7 | 30.7 (12.1)c | 56 (22)c | 0.05 |
NOTE: Values are the mean with SE in parenthesis. Treatment groups involved 5–10 female mice per experiment.
Abbreviations: NC, not calculated (different terminal timepoint than IV study); ND, not determined (below the analytic assay lower limit of quantitation).
aP < 0.01.
bP < 0.05.
cP < 0.001.
dNot significant.
eSteady-state.