TABLE 3

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.

SpeciesDose LevelProfile DayNumber of DosesTmaxCmaxAUC0–24 hAUC0–48 ht1/2CL/Fa
hµg/mlµg⋅h/mlµg⋅h/mldayml/h⋅kg
Mouse3 mg/kg110.52.18NC3.34NC897
4290.52.13NC4.81NC623
Rat0.2 mg/kg921410.03620.2340.295NC469
1 mg/kg92140.50.7712.973.39NC223
5 mg/kg9214112.143.148NC70.2
Rat (3H) Plasma5 mg/kg1116.9634.540.81.2697.7
Blood5 mg/kg1115.1326.229.84.95104
Monkey3 mg/kg112 (1 to 2)9.78 ± 1.8642.6 ± 6.0545.4 ± 6.2612.7b67.3 ± 9.16
182282 (1 to 2)6.76 ± 1.5349.6 ± 8.2260.4 ± 11.4NC51.2 ± 10.6
273412 (1–4)4.03 ± 2.2334.7 ± 14.143 ± 17.8NC78.6 ± 25.4
4 mg/kg4293 (1–4)12.1 ± 4.20NC83.3 ± 15.6NC49.5 ± 8.89
91163 (2–8)12.5 ± 3.68NC92.0 ± 29.8NC46.5 ± 11.4
Human100 mg114 (3–6)2.05 ± 0.97920.9 ± 5.53NCNCNC
2263 (3 to 4)2.9 ± 1.4324.5 ± 9.32NC18.2 ± 10.854
200 mg112 (1.5–3)4.01 ± 0.81449.1 ± 1.68NCNCNC
2263 (3 to 4)4.12 ± 0.7250.7 ± 6.48NC11.7 ± 3.241.5
400 mg113.5 (1.5–4)10.2 ± 3.06128 ± 40.3NCNCNC
2264 (3–6)9.56 ± 3.52122 ± 39.8NC13.9 ± 5.031
  • 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.