Table 2.
In Vivo Plasma Pharmacokinetic Parameters of 2 and 3a
| 2 |
3 |
2 |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| route/cpd. | model | doseb | CL(L/h/kg) | Vss(L/kg) | T1/2 (h) | Cmax (μM) | AUC0–24 (μM·h) | AUC0–24 (μM·h) | lung [2-NTP] (nmol/g) | F% | F% (solid) |
| iv 2c | rat | 1 | 1.36 ± 0.02 | 1.66 ± 0.06 | 1.03 ± 0.02 | 1.78 ± 0.28 | 2.50 ± 0.04 | ||||
| dog | 1 | 0.18 ± 0.01 | 0.33 ± 0.06 | 1.82 ±0.11 | 13.5 ± 2.9 | 18.7 ± 1.5 | |||||
| cyno | 20 | 0.56 ± 0.05 | 1.03 ± 0.09 | 2.68 ± 0.07 | 79.2 ± 6.7 | 123 ± 11 | 0.41 ± 0.09 | ||||
| AGM | 20 | 0.49 ± 0.12 | 0.89 ± 0.26 | 2.63 ± 0.19 | 87.3 ± 37.4 | 147 ± 36 | 0.23 ± 0.13 | ||||
| oral 2c | ratd | 5 | 1.87 ± 0.59 | 1.11 ± 0.30 | 3.97 ± 1.19 | 32 ± 10 | |||||
| dog | 5 | 4.18 ± 0.64 | 27.3 ± 3.5 | 83.4 ± 14.4 | 89 ± 15 | ||||||
| cyno | 5 | 3.31 ± 0.65 | 0.54 ± 0.28 | 1.67 ± 0.76 | 5.4 ± 2.5 | ||||||
| AGM | 5 | 6.65 ± 1.82 | 0.36 ± 0.05 | 3.15 ± 0.94 | 8.6 ± 2.5 | ||||||
| oral 3c | rat | 6 | 2.02 ± 0.33 | 2.10 ± 0.49 | 7.57 ± 0.53 | BLQ | 63 ± 4 | 90 ± 15 | |||
| dog | 14.4 | 3.62 ± 0.23 | 57.8 ± 11.3 | 202 ± 44 | 0.40 ± 0.04 | 93 ± 20 | 67 ± 12e | ||||
| cyno | 11.7 | 2.62 ± 0.55 | 7.57 ± 6.07 | 21.6 ± 11.0 | 0.01 ± 0.01 | 37 ± 19 | 18 ± 3e | ||||
| AGM | 14.4 | 3.19 ± 0.19 | 6.81 ± 3.08 | 26.6 ± 12.1 | 0.02 ± 0.02 | 31 ± 14 | |||||
| AGM | 60 | 2.90 ± 0.04 | 22.5 ± 1.3 | 129 ± 2 | 0.03 ± 0.03 | 0.31 ± 0.09 | 36 ± 1 | ||||
| AGM | 86.5 | 2.98 ± 0.22 | 19.6 ± 9.8 | 136 ± 67 | 0.68 ± 0.75 | 27 ± 13 | |||||
a
Doses and parameters shown are for the solution formulation. All studies are n = 3 animals unless noted.
b
Units mg/kg.
c
Formulations described in the Experimental Section.
d
For n = 6 animals.
e
Solid dosing was performed with Form III crystalline material with a mean particle size distribution of 203 μm (D90 = 385 μm). Cyno, cynomolgus monkey; AGM, African green monkey; BLQ, below limit of quantification.