TABLE 5.
Arithmetic means ± standard deviation of different pharmacokinetic parameters of day 1, day 7 and day 14 of the MAD study, measured in plasma. All PK doses were in fasted state. MAD, multiple ascending dose
| MAD pharmacokinetics in plasma | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1 | Day 7 | Day 14 | ||||||||||
| LTI‐291 dose | 3 mg (n = 7) | 10 mg (n = 8) | 30 mg (n = 8) | 60 mg (n = 8) | 3 mg (n = 7) | 10 mg (n = 8) | 30 mg (n = 8) | 60 mg (n = 8) | 3 mg (n = 7) | 10 mg (n = 8) | 30 mg (n = 8) | 60 mg (n = 8) |
| Cmax (ng/mL) | 91 ± 18 | 316 ± 80 | 927 ± 340 | 2070 ± 702 | 145 ± 33 | 516 ± 109 | 1610 ± 186 | 3290 ± 891 | 159 ± 47 | 509 ± 141 | 1510 ± 204 | 3200 ± 1070 |
| Cmin (ng/mL) | 32 ± 9 | 92 ± 18 | 312 ± 22 | 547 ± 109 | 77 ± 30 | 237 ± 70 | 797 ± 183 | 1580 ± 368 | 95 ± 38 | 239 ± 56 | 847 ± 220 | 1650 ± 493 |
| t½ (h) | 35.2 ± 30.2 | 20.9 ± 3.0 | 27.4 ± 9.9 | 26.0 ± 7.5 | 32.6 ± 13.1 | 29.9 ± 9.9 | 26.2 ± 5.0 | 38.6 ± 17.7 | 40.1 ± 19.7 | 33.0 ± 8.3 | 96.9 ± 72.5 | 33.5 ± 6.9 |
| λz (h−1) | 0.0296 ± 0.017 | 0.0338 ± 0.0051 | 0.0280 ± 0.0090 | 0.0287 ± 0.0088 | 0.0231 ± 0.0093 | 0.0251 ± 0.0072 | 0.0276 ± 0.0071 | 0.0206 ± 0.0069 | 0.0207 ± 0.0089 | 0.0222 ± 0.0053 | 0.0128 ± 0.013 | 0.0214 ± 0.0042 |
| AUC0–24 (ng*h/mL) | 1060 ± 182 | 3450 ± 625 | 10 700 ± 1470 | 19 900 ± 4080 | 2010 ± 805 | 7900 ± 1750 | 26 900 ± 4930 | 53 000 ± 10 200 | 2900 ± 896 | 7650 ± 1580 | 26 500 ± 4410 | 52 300 ± 13 800 |
| CL/F (L) | 1.41 ± 0.77 | 1.66 ± 0.29 | 1.35 ± 0.29 | 1.59 ± 0.50 | 1.63 ± 0.65 | 1.33 ± 0.32 | 1.15 ± 0.22 | 1.17 ± 0.25 | 1.14 ± 0.41 | 1.36 ± 0.28 | 1.17 ± 0.24 | 1.21 ± 0.27 |
| Vz/F (L) | 49.9 ± 9.1 | 49.4 ± 8.0 | 50.4 ± 9.4 | 56.2 ± 11.9 | 70.5 ± 0.0322 | 54.7 ± 12.5 | 42.2 ± 5.2 | 61.3 ± 17.3 | 60.3 ± 16.2 | 63.6 ± 15.8 | 149 ± 95.6 | 57.2 ± 12.7 |
| Cmax/dose (ng/mL/mg) | 30.2 ± 5.9 | 31.6 ± 8.0 | 30.9 ± 11.3 | 34.5 ± 11.7 | 48.2 ± 11.1 | 51.6 ± 10.9 | 53.6 ± 6.19 | 54.9 ± 14.9 | 53.0 ± 15.5 | 50.9 ± 14.1 | 50.4 ± 6.8 | 53.3 ± 17.9 |
| AUC0–24/dose (ng*h/mL/mg) | 353.3 ± 60.7 | 345.0 ± 62.5 | 356.7 ± 49.0 | 331.7 ± 68.0 | 670.0 ± 268.3 | 790.0 ± 175.0 | 896.7 ± 164.3 | 883.3 ± 170.0 | 966.7 ± 298.7 | 765.0 ± 158.0 | 883.3 ± 147.0 | 871.7 ± 230.0 |
| Median T max (h) (min, max) | 2.0 (1.0, 4.0) | 1.0 (1.0, 2.0) | 1.0 (1.0, 8.0) | 1.0 (1.0, 8.1) | 4.0 (1.0, 4.0) | 1.0 (1.0, 8.0) | 1.5 (1.0, 4.0) | 1.0 (1.0, 4.0) | 1.0 (1.0, 8.8) | 1.1 (1.0, 8.0) | 1.5 (1.0, 8.0) | 1.0 (1.0, 2.0) |
| Accumulation index | ‐ | ‐ | ‐ | ‐ | 2.51 ± 0.77 | 2.35 ± 0.58 | 2.13 ± 0.28 | 2.86 ± 1.05 | 2.95 ± 1.17 | 2.53 ± 0.49 | 6.35 ± 4.34 | 2.56 ± 0.41 |