Pharmacokinetics characterization of rVIII-SingleChain alone or coadministered with rD′D3-FP
| Parameter . | Treatment . | FVIII-ko mouse . | VWF-ko mouse . | NMRI mouse . | Rat . | Rabbit . | Cynomolgus monkey . | |
|---|---|---|---|---|---|---|---|---|
| Measured by: . | FVIII:chr . | FVIII:Ag . | FVIII:Ag . | FVIII:Ag . | FVIII:Ag . | FVIII:Ag . | FVIII:chr . | |
| CL, mL/h/kg | rVIII-SingleChain | 3.6 | 3.4 | n.d. | 25.8 | 8.3 | 3.7 | 2.0 |
| rVIII-SingleChain + rD′D3-FP | 1.3-2.9 | 1.3-3.1 | 1.7 | 3.5 | 1.7-4.9 | 1.0-1.8 | 0.4-0.4 | |
| Fold difference | 1.3-2.8* | 1.1-2.6* | n.a. | 7.4† | 1.7-4.9* | 2.1-3.7* | 4.5-5.5* | |
| MRT, h | rVIII-SingleChain | 10.1 | 14.0 | n.d. | 2.0 | 7.4 | 23.0 | 19.9 |
| rVIII-SingleChain + rD′D3-FP | 11.4-32.7 | 23.0-44.0 | 31.0 | 18.0 | 10.5-29.6 | 33.0-64.0 | 85.3-99.0 | |
| Fold difference | 1.1-3.2† | 1.6-3.1† | n.a. | 8.9* | 1.4-4.0† | 1.4-2.8† | 4.3-5.0† | |
| t1/2, h | rVIII-SingleChain | 7.0 | 10.0 | n.d. | 1.4 | 5.2 | 17.0 | 13.1 |
| rVIII-SingleChain + rD′D3-FP | 7.9-34.3 | 19.0-31.0 | 21 | 13 | 7.1-20.3 | 21.0-44.0 | 56.1-66.1 | |
| Fold difference | 1.1-4.9† | 1.9-3.1† | n.a. | 9.1* | 1.4-3.9† | 1.2-2.6† | 4.3-5.0† | |
| Parameter . | Treatment . | FVIII-ko mouse . | VWF-ko mouse . | NMRI mouse . | Rat . | Rabbit . | Cynomolgus monkey . | |
|---|---|---|---|---|---|---|---|---|
| Measured by: . | FVIII:chr . | FVIII:Ag . | FVIII:Ag . | FVIII:Ag . | FVIII:Ag . | FVIII:Ag . | FVIII:chr . | |
| CL, mL/h/kg | rVIII-SingleChain | 3.6 | 3.4 | n.d. | 25.8 | 8.3 | 3.7 | 2.0 |
| rVIII-SingleChain + rD′D3-FP | 1.3-2.9 | 1.3-3.1 | 1.7 | 3.5 | 1.7-4.9 | 1.0-1.8 | 0.4-0.4 | |
| Fold difference | 1.3-2.8* | 1.1-2.6* | n.a. | 7.4† | 1.7-4.9* | 2.1-3.7* | 4.5-5.5* | |
| MRT, h | rVIII-SingleChain | 10.1 | 14.0 | n.d. | 2.0 | 7.4 | 23.0 | 19.9 |
| rVIII-SingleChain + rD′D3-FP | 11.4-32.7 | 23.0-44.0 | 31.0 | 18.0 | 10.5-29.6 | 33.0-64.0 | 85.3-99.0 | |
| Fold difference | 1.1-3.2† | 1.6-3.1† | n.a. | 8.9* | 1.4-4.0† | 1.4-2.8† | 4.3-5.0† | |
| t1/2, h | rVIII-SingleChain | 7.0 | 10.0 | n.d. | 1.4 | 5.2 | 17.0 | 13.1 |
| rVIII-SingleChain + rD′D3-FP | 7.9-34.3 | 19.0-31.0 | 21 | 13 | 7.1-20.3 | 21.0-44.0 | 56.1-66.1 | |
| Fold difference | 1.1-4.9† | 1.9-3.1† | n.a. | 9.1* | 1.4-3.9† | 1.2-2.6† | 4.3-5.0† | |
Data are shown for mice and for FVIII-competent rats, rabbits, and cynomolgus monkeys, as well as their respective improvement over coadministered human pdVWF.
The following doses were used:
FVIII-ko mice: rVIII-SingleChain, 100 IU/kg and rD′D3-FP, 0.286-28.6 mg/kg
VWF-ko mice: rVIII-SingleChain, 100 IU/kg and rD′D3-FP, 2.86 mg/kg
NMRI mice: rVIII-SingleChain, 100 IU/kg and rD′D3-FP, 2.86-28.6 mg/kg
Rats: rVIII-SingleChain, 200 IU/kg and rD′D3-FP, 0.14-28.6 mg/kg
Rabbits: rVIII-SingleChain, 150 IU/kg and rD′D3-FP, 1.4-8.6 mg/kg
Cynomolgus monkeys: rVIII-SingleChain, 250 IU/kg and rD′D3-FP, 7.2-28.6 mg/kg; FVIII activity was corrected for endogenous levels.
FVIII:Ag, FVIII antigen assay; FVIII:chr, FVIII chromogenic assay; n.a., not applicable; n.d., not done.
Fold decrease.
Fold increase over rVIII-SingleChain.