Table 3.
Gilteritinib pharmacokinetic parameters after single (Day-2) and multiple administrations (Day 15), CHRYSALIS
| Single dose | |||||||
|---|---|---|---|---|---|---|---|
| Parameter | 20 mg (n = 5) | 40 mg (n = 3) | 80 mg (n = 3) | 120 mg (n = 3) | 200 mg (n = 3) | 300 mg (n = 3) | 450 mg (n = 3)a |
| Cmax (ng/mL) | |||||||
| Mean (SD) | 28.1 (21.5) | 25.0 (14.6) | 75.3 (25.2) | 137 (94.4) | 168 (45.3) | 204 (136) | 208 (51.8) |
| Median (range) | 23.7 (7.5–64.5) | 16.99 (16.3–41.8) | 71.5 (52.2–102) | 85.7 (78.9–246) | 149 (136–220) | 137 (115–361) | 216 (152–255) |
| AUC24 (ng·h/mL) | |||||||
| Mean (SD) | 302 (207) | 360 (223.5) | 1216 (473) | 2480 (1972) | 3022 (844) | 4163 (3178) | 3324 (221.1) |
| Median (range) | 262 (98.5–642) | 315 (163–603) | 995 (895–1759) | 1393 (1291–4756) | 2538 (2533–3997) | 2446 (2214–7830) | 3324 (3168–3480) |
| Tmax (h) | |||||||
| Median (range) | 2.0 (0.50–4.0) | 5.98 (3.97–24.0) | 4.0 (4.0–4.1) | 2.1 (2.0–3.8) | 5.2 (4.0–5.97) | 6.1 (4.1–24.1) | 5.8 (4.1–5.92) |
| Multiple dosing | |||||||
|---|---|---|---|---|---|---|---|
| Parameter | 20 mg (n = 4)b | 40 mg (n = 3)c | 80 mg (n = 3) | 120 mg (n = 3) | 200 mg (n = 2) | 300 mg (n = 3) | 450 mg (n = 1) |
| Cmax (ng/mL) | |||||||
| Mean (SD) | 64.6 (48.8) | 108 (31.92) | 376 (150.5) | 374 (190) | 1462 (815) | 1525 (665) | 1528 |
| Median (range) | 45.6 (30.5–137) | 106 (76.7–140) | 396.3 (217–516) | 282 (248–593) | 1462 (886–2038) | 1257 (1036–2282) | |
| AUC24 (ng∙h/mL) | |||||||
| Mean (SD) | 1299 (1006) | 2482 (33.3) | 6958 (3273) | 6943 (3221) | 31,428 (21,412) | 31,005 (10,068) | 34,768 |
| Median (range) | 917.0 (540–2440) | 2482 (2458–2505) | 6234 (4108–10,532) | 6180 (4171–10,477) | 31,428 (16,288–46,568) | 28,711 (22,282–42,022) | |
| Tmax (h) | |||||||
| Median (range) | 4.0 (4.0–6.0) | 3.9 (0.50–6.0) | 4.3 (4.0–4.4) | 2.2 (1.95–5.75) | 6.0 (6.0–6.1) | 6.1 (4.1–6.1) | 5.93 |
| t½ (h) | |||||||
| Mean (SD) | 62.1 (17.9) | 152 (129.2) | 86.1 (24.1) | 45.9 (18.83) | 142 (61.5) | 142 (55.0) | NC |
| Median (range) | 54.46 (49.4–82.6) | 151.8 (60.5–243) | 91.03 (60.0–107) | 44.93 (27.5–65.1) | 142 (98.4–185) | 159 (80.7–187) | |
| Rac | |||||||
| Mean (SD) | 4.3 (1.069) | 9.6 (7.8) | 5.7 (1.4) | 3.3 (1.2) | 9.0 (3.7) | 9.1 (3.3) | NC |
| Median (range) | 3.8 (3.5–5.5) | 9.6 (4.2–15.1) | 6.0 (4.1–6.97) | 3.2 (2.2–4.4) | 9.0 (6.4–11.7) | 10.1 (5.4–11.7) | |
| Ctrough (ng/mL) | n = 11 | n = 12 | n = 20 | n = 61 | n = 79 | n = 15 | n = 1 |
| Mean (SD) | 43.5 (23.5) | 72.9 (40.1) | 165 (88.0) | 367 (253) | 816 (557) | 1242 (723) | 1170 |
| Median (range) | 43.4 (13.6–37.5) | 66.6 (26.7–166) | 110 (78.6–339) | 292 (77.1–1173) | 668 (90.5–2925) | 1085 (470–2391) | |
AUC24 area under the concentration–time curve from time of dosing to 24 h post-dose, Cmax maximum plasma concentration, Ctrough trough concentration, NC not calculated, Rac accumulation ratio, SD standard deviation, t½ elimination ratio (calculated from Rac), Tmax time to reach maximum concentration
an = 2 for AUC24
bn = 3 for AUC24, t½, and Rac
cn = 2 for AUC24, t½, and Rac