Table 5.

Pharmacokinetic parameters of rFVIIa and analogs administered as a single dose intravenously to NMRI mice


Treatment

Dose, mg/kg

t1/2, h

CL, mL/h/kg

Vz, mL/kg
rFVIIa   1   1.0   204   302  
  3   1.1   121   191  
  6   1.2   128   225  
  10   1.4   117   232  
FVIIaIIa  1   1.1   425   673  
  3   1.4   326   644  
K337A-FVIIaIIa  1   1.3   339   648  
  3   1.1   261   430  
M298Q-FVIIa   1   1.3   256   495  

 
3
 
1.3
 
262
 
476
 

Treatment

Dose, mg/kg

t1/2, h

CL, mL/h/kg

Vz, mL/kg
rFVIIa   1   1.0   204   302  
  3   1.1   121   191  
  6   1.2   128   225  
  10   1.4   117   232  
FVIIaIIa  1   1.1   425   673  
  3   1.4   326   644  
K337A-FVIIaIIa  1   1.3   339   648  
  3   1.1   261   430  
M298Q-FVIIa   1   1.3   256   495  

 
3
 
1.3
 
262
 
476
 

Blood samples were drawn from 3 animals/time point at predose (time 0), 2, 5, 10, 20, 40 minutes, 1, 2, 3, and 4 hours. Plasma samples were analyzed for content of rFVIIa and FVIIaIIa, K337A-FVIIaIIa, and M298Q-FVIIa, and the following parameters were estimated: terminal plasma elimination half-life (t1/2), based on the natural logarithm of 2 divided by the slope of the log-linear regression of the concentration versus time (λz). The total body clearance (CL) was determined as dose divided by area under the plasma concentration curve (AUC) from zero to infinity. The volume of distribution based on the terminal phase (Vz) was estimated by dose divide by AUC times λz. The clearance and volume of distribution (Vz) was higher for the analogs than for rFVIIa, increasing in the order FVIIa < M298Q-FVIIa < K337A-FVIIaIIa < FVIIaIIa. A comparison of these parameters at the same dose of rFVIIa and rFVIIa analogs reveals approximately a 2- to 3-fold increase of the values obtained for the analogs. All mice treated with either rFVIIa or one of the 3 analogs were exposed to the drug up to 4 hours after dosage.

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