Table 3.
ATI-450 Pharmacokinetic Parameters
| Parameter | Single Ascending Dose Group | Multiple Ascending Dose Group | |||||
|---|---|---|---|---|---|---|---|
| ATI-450 10 mg (n=6) | ATI-450 30 mg (n=6)a | ATI-450 50 mg (n=6) | ATI-450 100 mg (n=6) | ATI-450 10 mg BID (n=8) | ATI-450 30 mg BID (n=8) | ATI-450 50 mg BID (n=8) | |
| Cmax, ng/mL | 39.4 ± 10.4 | 122.0 ± 33.4 | 160.7 ± 20.4 | 426.0 ± 110.6 | 51.8 ± 15.8 | 146.5 ± 33.6 | 219.0 ± 77.8 |
| tmax, hb | 2.0 (2.0–4.0) | 4.0 (2.0–4.1) | 3.0 (2.0–4.0) | 2.0 (2.0–4.0) | 2.0 (2.0–2.0) | 2.0 (1.0–4.0) | 3.0 (1.0–4.0) |
| AUC0-t, h*ng/mL | 276.3 ± 77.8 | 1074.0 ± 243.5a | 1430.0 ± 254.0 | 3489.8 ± 475.7 | 364.6 ± 110.7 | 1204.6 ± 309.1 | 2260.3 ± 1074.7 |
| AUC0-inf, h*ng/mL | 285.3 ± 78.4 | 1102.4 ± 247.4a | 1464.7 ± 269.5 | 3654.8 ± 522.9 | N/A | N/A | N/A |
| AUCtau, h*ng/mL | N/A | N/A | N/A | N/A | 287.8 ± 81.5 | 908.9 ± 163.1 | 1507.8 ± 659.9 |
| t1/2, h | 8.5 ± 3.2 | 10.7 ± 3.3a | 9.1 ± 2.4 | 11.2 ± 5.8 | 9.6 ± 2.1 | 10.3 ± 3.2 | 11.6 ± 3.7 |
| CL/F or CLss/F,c L/h | 37.0 ± 8.8 | 28.4 ± 7.1a | 35.1 ± 6.3 | 27.9 ± 4.3 | 37.4 ± 10.9 | 33.9 ± 5.9 | 37.3 ± 11.7 |
| Vz/F or Vss/F,c L | 430.2 ± 124.0 | 451.4 ± 201.5a | 445.0 ± 94.7 | 439.8 ± 189.7 | 517.4 ± 203.2 | 483.1 ± 85.1 | 586.4 ± 163.2 |
| Ctrough, ng/mLd | |||||||
| Day 2 | N/A | N/A | N/A | N/A | 10.1 ± 4.7 | 37.5 ± 18.8 | 84.0 ± 40.6 |
| Day 3 | N/A | N/A | N/A | N/A | 9.8 ± 4.5 | 44.1 ± 29.3 | 80.6 ± 44.2 |
| Day 4 | N/A | N/A | N/A | N/A | 9.2 ± 5.0 | 36.8 ± 14.9 | 81.5 ± 49.6 |
| Day 5 | N/A | N/A | N/A | N/A | 9.6 ± 4.7 | 34.9 ± 13.8 | 81.5 ± 43.9 |
| Day 6 | N/A | N/A | N/A | N/A | 10.7 ± 4.9 | 38.9 ± 16.2 | 76.4 ± 38.6 |
| Cmin, ng/mL | N/A | N/A | N/A | N/A | 8.1 ± 3.1 | 28.8 ± 10.7 | 58.7 ± 32.8 |
| Cavg, ng/mL | N/A | N/A | N/A | N/A | 24.0 ± 6.8 | 75.6 ± 13.4 | 125.6 ± 55.0 |
| Rac, Cmax | N/A | N/A | N/A | N/A | 1.6 ± 0.6 | 1.2 ± 0.3 | 1.3 ± 0.5 |
| Rac, AUCtau | N/A | N/A | N/A | N/A | 1.4 ± 0.3 | 1.4 ± 0.3 | 1.3 ± 0.4 |
Notes: Data presented are means ± SD unless otherwise indicated. aOne subject was excluded for AUC0-t, AUC0-inf, t1/2, CL/F, and Vz/F measurements due to withdrawn consent. No samples were collected past 12 hours. bData presented are medians (ranges). cValues for CL/F and Vz/F are for single doses and values for CLss/F and Vss/F are for multiple doses. dCtrough values are presented for day 2 through day 6 for the MAD cohorts.
Abbreviations: AUC0-inf, area under the plasma concentration–time curve from time 0 to time infinity; AUC0-t, area under the plasma concentration–time curve from time 0 to time t; AUCtau, area under the plasma concentration–time curve over the 12-hour dosing interval, tau; BID, twice daily; CL/F, clearance; CLss/F, clearance at steady state; Cavg, average plasma concentration after multiple dosing, on day 7; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; Ctrough, measured concentration at the end of a dosing interval; N/A, not applicable; Rac, AUCtau, accumulation ratio for AUCtau; Rac, Cmax, accumulation ratio for Cmax; t1/2, terminal elimination half-life; tmax, time to maximum plasma concentration; Vss/F, volume of distribution at steady state; Vz/F, volume of distribution.