Table 3.
Geometric mean (%CV) for derived PK parameters after a single oral dose in MONARCH 1 (JPBN), MONARCH 2 (JPBL), and MONARCH 3 (JPBM) and comparison with previous analyses
| Parameter | Semimechanistic model development | External validation with phase III data | NCA(200 mg) | ||||
|---|---|---|---|---|---|---|---|
|
200 mg N = 421 |
Healthy subjects 200 mg N = 65 |
JPBN (patients) 200 mg N = 132 |
JPBL (patients) 200 mg N = 142 |
JPBL (patients) 150 mg N = 326 |
JPBM (patients) 150 mg N = 322 |
N = 8 |
|
| Parent | |||||||
| Bioavailability (F) | 0.482 (20.1) | 0.462 (17.9) | 0.426 (15.3) | 0.466 (16.8) | 0.494 (14.5) | 0.516 (12.9) | 0.448 (19) |
| Hepatic clearance (L/h) | 21.8 (39.8) | 23.8 (30.3) | 24.3 (24.9) | 26 (25.7) | 25.1 (21) | 23 (26.7) | 24.0 (27) |
| Half‐life (h) c , c | 24.8 (52.1) | 25.5 (25.8) | 25.8 (55.4) | 17.7 (54) | 17.5 (46) | 20.3 (43) | 29.3 (18) |
| AUC0−∞ (ng·h/mL) | 4420 (58.6) | 3890 (47.1) | 3510 (38.0) | 3580 (39.5) | 2960 (32.2) | 3360 (36.6) | 3730 (31) |
| Cmax (ng/mL) | 123 (77.1) | 113 (48.4) | 86.9 (59.4) | 141 (67.5) | 123 (59.9) | 125 (54.6) | 114 (32) |
| M2 | |||||||
| Apparent hepatic clearance (L/h) | 21.5 (54.3) | 22.9 (28.4) | 23.9 (35.3) | 20.9 (48.1) | 18.3 (49.9) | 21.6 (50.4) | NA |
| Half‐life (h) | 19.3 (65.4) | 21.2 (25.8) | 21.3 (73.5) | 16 (73.6) | 17.2 (65.1) | 16 (68.9) | 72.6 (23) |
| AUC0−∞ (ng.h/mL) | 1790 (71.6) | 1690 (39.9) | 1620 (55.0) | 1820 (72) | 1640 (70.2) | 1290 (75.8) | 1450 (19) |
| Cmax (ng/mL) | 30.3 (75.7) | 28.8 (36.1) | 26.9 (54.7) | 40.2 (73.9) | 33.6 (70.4) | 26.8 (68) | 31.7 (22) |
| M20 | |||||||
| Apparent hepatic clearance (L/h) | 23.7 (52.1) | 23.9 (23.7) | 26.2 (33.5) | 25.8 (43.3) | 22.5 (44.3) | 26 (46.4) | NA |
| Half‐life (h) | 17.5 (62.5) | 20.3 (21.3) | 19.4 (72.7) | 13 (70.1) | 14 (62.5) | 13.3 (65.6) | 35.3 (16) |
| AUC0−∞ (ng·h/mL) | 3240 (74.7) | 3450 (34.4) | 2750 (55.0) | 3020 (72.8) | 2870 (69.6) | 2300 (74.4) | 3260 (26) |
| Cmax (ng/mL) | 48.8 (83.0) | 49.1 (32.5) | 39.4 (56.0) | 66.1 (82.8) | 59.3 (78.7) | 45.7 (72) | 55.7 (26) |
%CV, coefficient of variation; AUC0−∞, area under the curve from 0 to infinity; Cmax, maximum plasma concentration; i.v., intravenous; JPBL, MONARCH 2; JPBM, MONARCH 3; JPBN, MONARCH 1; NA, not applicable; NCA, noncompartmental analysis.
Absolute bioavailability study that had 13C8‐abemaciclib administered i.v.
Absolute bioavailability study that had 13C8‐abemaciclib administered i.v.
Approximated as 0.693*(Vc+Vp)/CL, where Vc is the central volume, Vp is peripheral volume, and CL is the total hepatic clearance.