Table 4. Pharmacokinetic parameters of M-I after single and multiple oral dosing of TAK-285.
|
Dose level of TAK-285
|
||||||
|---|---|---|---|---|---|---|
| Parameters | 50 mg q.d.a | 50 mg b.i.d.a | 100 mg b.i.d.a | 200 mg b.i.d.a | 300 mg b.i.d.a | 300 mg b.i.d.b |
| Single dosing | ||||||
| N | 4 | 3 | 3 | 4 | 4 | 6 |
| Cmax (ng ml–1) | 57.2 (11.7) | 62.6 (16.4) | 165 (35.4) | 313 (106) | 383 (79.9) | 272 (190) |
| AUC0–∞ (ng × h ml–1) | 401 (79.3) | 494 (174) | 1340 (350) | 2870 (242) | 3230 (911) | 2710 (1690) |
| Tmax (h) | 1.49 (1.00–2.00) | 2.00 (1.00–2.02) | 2.00 (2.00–4.00) | 2.00 (2.00–4.05) | 2.00 (2.00–2.00) | 2.50 (2.00–3.00) |
| t1/2 (h) | 8.32 (2.83) | 7.54 (1.21) | 9.70 (4.51) | 7.40 (1.45) | 10.0 (1.96) | 6.99 (2.53) |
| Multiple dosing c | ||||||
| N | 3 | 3 | 3 | 3 | 3 | 6 |
| Cmax (ng ml–1) | 68.0 (12.4) | 96.1 (53.2) | 302 (62.9) | 767 (258) | 549 (123) | 584 (349) |
| AUC0–tau (ng × h ml–1) | 523 (26.3) | 786 (451) | 2660 (902) | 6410 (3330) | 4750 (1020) | 5600 (3480) |
| Tmax (h) | 2.00 (1.00–2.02) | 2.05 (2.00–3.00) | 3.00 (3.00–4.05) | 2.05 (2.00–3.00) | 2.00 (2.00–2.02) | 2.99 (0.500–3.98) |
| t1/2 (h) | 11.8 (3.99) | 9.57 (2.11) | 10.0 (2.38) | 8.53 (1.42) | 14.0 (3.17) | 14.3 (7.44) |
| R (Cmax) | 1.19 (0.202) | 1.49 (0.526) | 1.90 (0.651) | 2.73 (2.02) | 1.58 (0.456) | 2.64 (1.41) |
| R (AUC) | 1.40 (0.216) | 2.27 (0.896) | 2.99 (0.740) | 3.58 (2.23) | 2.42 (0.859) | 3.68 (1.99) |
Abbreviations: AUC=area under the plasma concentration-time curve from time zero to infinity (0–∞) or to dosing interval (0–tau); b.i.d.= twice daily; Cmax=maximal observed plasma concentration after dosing; q.d.= once daily; R=accumulation ratio of Cmax or AUC between multiple versus single dosing; R (AUC)=AUC0–tau (treatment day D)/AUC0–12 (treatment day 1) (dose escalation cohort: D=21, repeated administration cohort: D=28); Tmax=time to reach the maximal plasma concentration; t1/2=estimated terminal-phase half-life.
All parameters are reported as mean (±s.d.) values, except for Tmax that is reported as a median (range) value.
a
Dose escalation cohort.
b
Repeated administration cohort.
c
Day 21 or day 28.