Comparison of selected pharmacokinetic parameters across species of volanesorsen following subcutaneous injections
Plasma pharmacokinetic parameters [mean ± S.D.; Tmax, median (minimum-maximum)] for mice and rats were calculated by noncompartmental methods using the sparse sampling function. Rat (3H)-volanesorsen study concentrations are expressed as microgram equivalents of volanesorsen per milliliter.
| Species | Dose Level | Profile Day | Number of Doses | Tmax | Cmax | AUC0–24 h | AUC0–48 h | t1/2 | CL/Fa |
|---|---|---|---|---|---|---|---|---|---|
| h | µg/ml | µg⋅h/ml | µg⋅h/ml | day | ml/h⋅kg | ||||
| Mouse | 3 mg/kg | 1 | 1 | 0.5 | 2.18 | NC | 3.34 | NC | 897 |
| 42 | 9 | 0.5 | 2.13 | NC | 4.81 | NC | 623 | ||
| Rat | 0.2 mg/kg | 92 | 14 | 1 | 0.0362 | 0.234 | 0.295 | NC | 469 |
| 1 mg/kg | 92 | 14 | 0.5 | 0.771 | 2.97 | 3.39 | NC | 223 | |
| 5 mg/kg | 92 | 14 | 1 | 12.1 | 43.1 | 48 | NC | 70.2 | |
| Rat (3H) Plasma | 5 mg/kg | 1 | 1 | 1 | 6.96 | 34.5 | 40.8 | 1.26 | 97.7 |
| Blood | 5 mg/kg | 1 | 1 | 1 | 5.13 | 26.2 | 29.8 | 4.95 | 104 |
| Monkey | 3 mg/kg | 1 | 1 | 2 (1 to 2) | 9.78 ± 1.86 | 42.6 ± 6.05 | 45.4 ± 6.26 | 12.7b | 67.3 ± 9.16 |
| 182 | 28 | 2 (1 to 2) | 6.76 ± 1.53 | 49.6 ± 8.22 | 60.4 ± 11.4 | NC | 51.2 ± 10.6 | ||
| 273 | 41 | 2 (1–4) | 4.03 ± 2.23 | 34.7 ± 14.1 | 43 ± 17.8 | NC | 78.6 ± 25.4 | ||
| 4 mg/kg | 42 | 9 | 3 (1–4) | 12.1 ± 4.20 | NC | 83.3 ± 15.6 | NC | 49.5 ± 8.89 | |
| 91 | 16 | 3 (2–8) | 12.5 ± 3.68 | NC | 92.0 ± 29.8 | NC | 46.5 ± 11.4 | ||
| Human | 100 mg | 1 | 1 | 4 (3–6) | 2.05 ± 0.979 | 20.9 ± 5.53 | NC | NC | NC |
| 22 | 6 | 3 (3 to 4) | 2.9 ± 1.43 | 24.5 ± 9.32 | NC | 18.2 ± 10.8 | 54 | ||
| 200 mg | 1 | 1 | 2 (1.5–3) | 4.01 ± 0.814 | 49.1 ± 1.68 | NC | NC | NC | |
| 22 | 6 | 3 (3 to 4) | 4.12 ± 0.72 | 50.7 ± 6.48 | NC | 11.7 ± 3.2 | 41.5 | ||
| 400 mg | 1 | 1 | 3.5 (1.5–4) | 10.2 ± 3.06 | 128 ± 40.3 | NC | NC | NC | |
| 22 | 6 | 4 (3–6) | 9.56 ± 3.52 | 122 ± 39.8 | NC | 13.9 ± 5.0 | 31 |
AUC0–24 h, AUC from 0 to 24 hours; AUC0–48 h, AUC from 0 to 48 hours; CL, clearance; F, bioavailability; NC, not calculated; PK, pharmacokinetic; Tmax, time to reach Cmax.
↵a CL0–48 h/F = [dose (mg/kg)/AUC0–48h (µg*h/ml)] × 1000 for mouse. CL0–168 h/F = [dose (mg/kg)/AUC0–168 h (µg*h/ml)] × 1000 for rat. CL0–48 h/F = [dose (mg/kg)/AUC0–48 h (µg*h/ml)] × 1000 for monkey. CL0–48 h/F = [dose (mg/kg)/AUC0–24 h (µg*h/ml)] × 1000 for human.
↵b Half-life reported in monkeys is for the 8 mg/kg group, which was the lowest dose that could be calculated.