Table 1.
Plasma pharmacokinetic variables of ACT‐389949 after administration of single doses of 1, 5, 20, 50, 100, 200, 500 and 1000 mg or multiple doses of 40, 200 and 800 mg of ACT‐389949 once daily (o.d.), every other day (q2d) and every 3 days (q3d)
| Dose | Period | N | C max (ng ml −1 ) | t max (h) | AUC a (ng*h ml −1 ) | t 1/2 (h) | AI AUC τ b | AI C max b |
|---|---|---|---|---|---|---|---|---|
| Single‐ascending dose study (SAD) | ||||||||
| 1 mg | ‐ | 6 | 10.2 (6.7, 15.6) | 1.3 (0.7–3.0) | 57.4 (44.4, 74.1) | 33.9 (21.2, 54.1) | – | – |
| 5 mg | ‐ | 6 | 39.6 (30.3, 51.8) | 2.0 (0.5–4.0) | 446 (310, 641) | 22.6 (12.5, 41.2) | – | – |
| 20 mg | ‐ | 6 | 146 (117, 183) | 1.5 (1.5–3.0) | 1295 (1039, 1614) | 30.4 (16.2, 56.9) | – | – |
| 50 mg | ‐ | 6 | 304 (230, 402) | 1.5 (0.7–2.0) | 3479 (2664, 4545) | 24.2 (15.4, 38.2) | – | – |
| 100 mg | ‐ | 6 | 223 (158, 315) | 1.8 (1.0–6.0) | 4059 (3581, 4602) | 21.3 (16.5, 27.5) | – | – |
| 200 mg | ‐ | 7 | 393 (264, 585) | 3.0 (1.5–4.0) | 7940 (5499, 11 464) | 38.8 (21.6, 69.9) | – | – |
| 500 mg | ‐ | 6 | 656 (477, 901) | 3.5 (1.5–4.0) | 13 137 (9750, 17 699) | 28.0 (17.0, 46.1) | – | – |
| 1000 mg | ‐ | 6 | 843 (619, 1147) | 2.5 (1.5–24.0) | 24 850 (18 460, 33 454) | 33.4 (14.6, 76.4) | – | – |
| Multiple‐ascending dose study (MAD) | ||||||||
| 40 mg o.d. | Day 1 | 10 | 281 (229, 345) | 1.75 (1.0–4.0) | 1795 (1547, 2081) | – | – | – |
| Day 7 | 10 | 417 (348, 498) | 1.5 (1.0–4.0) | 4013 (3269, 4926) | – | 2.2 (1.9, 2.6) | 1.5 (1.2, 1.8) | |
| 40 mg q2d | Day 1 | 10 | 275 (200, 379) | 1.0 (1.0–2.0) | 2652 (2262, 3109) | – | – | – |
| Day 7 | 10 | 280 (228, 345) | 2.0 (1.0–4.0) | 3950 (3350, 4657) | – | 1.5 (1.3, 1.7) | 1.0 (0.7, 1.4) | |
| 200 mg o.d. | Day 1 | 10 | 401 (310, 544) | 1.75 (1.5–4.0) | 3276 (2476, 4334) | – | – | – |
| Day 7 | 10 | 912 (750, 1108) | 2.0 (1.5–4.0) | 10 759 (8250, 14 032) | – | 3.3 (2.7, 4.0) | 2.2 (1.7, 2.9) | |
| 200 mg q3d | Day 1 | 10 | 551 (408, 745) | 2.0 (1.5–4.0) | 11 355 (8692, 14 834) | – | – | – |
| Day 10 | 10 | 736 (580, 934) | 2.0 (1.5–4.0) | 16 651 (12 503, 22 175) | – | 1.5 (1.2, 1.8) | 1.3 (1.1, 1.6) | |
| 800 mg o.d. | Day 1 | 10 | 639 (469, 870) | 2.0 (1.5–24.0) | 6633 (5114, 8605) | – | – | – |
| Day 7 | 10 | 1281 (1019, 1610) | 4.0 (1.5–4.0) | 17 488 (13 933, 21 950) | – | 2.6 (2.2, 3.1) | 2.0 (1.6, 2.5) | |
| Overall (geometric means and 95 % CI) | – | – | – | 29.3 (25.5, 33.7) | 2.1 (1.9, 2.4) | 1.6 (1.4, 1.8) | ||
Data are expressed as geometric means (and 95% CI) or for tmax as median (and range). AI, accumulation index; AUCτ, area under the plasma concentration–time curve over one dosing interval; CI, confidence interval; Cmax, maximum plasma concentration; t1/2, ; tmax, maximum plasma concentration
Area under the plasma concentration–time curve from zero to time t of the last measured concentration above the limit of quantification (24 h or 48 h postdose for 1 mg and 60 h postdose for 5–1000 mg) for single doses (SAD) and during the dosing interval τ for multiple dosing (MAD); τ is 24 h for all o.d. dosing regimens, 48 h for q2d dosing and 72 h for q3d dosing
Accumulation index = AUCτ Day 7(10)/AUCτ Day 1, Cmax Day 7(10)/Cmax Day 1