-P includes multiple processing steps that reduce the risk of virus transmission. The manufacturing process has been demonstrated to reduce the risk of virus transmission in an additive manner: 1) cryoprecipitation; 2) Al(OH)3 adsorption, glycine precipitation, and NaCl precipitation, studied in combination; and 3) pasteurization in aqueous solution at 60°C for 10 hours. Total mean cumulative virus reductions ranged from 6.0 to ≥11.3 log10 as shown in Table 7.
Table 7: Mean Virus Reduction Factors Virus Studied Cryoprecipitation Al(OH)3 Adsorption / Glycine Precipitation / NaCl Precipitation Pasteurization Mean Cumulative Virus Reduction
[log10] [log10] [log10] [log10]
ND, not determined; NA, not applicable; HIV-1, human immunodeficiency virus type 1, model for HIV types 1 and 2; BVDV, bovine viral diarrhea virus, model for HCV and WNV; PRV, pseudorabies virus, model for large enveloped DNA viruses (e.g., herpes virus); WNV, West Nile virus; HAV, hepatitis A virus; and CPV, canine parvovirus, model for Parvovirus B19 virus (B19V).
*
The virus eva luation studies for B19V employed a novel experimental infectivity assay using a clone of the cell line UT7 that contains erythropoietic progenitor cells; (residual) virus titer was determined using an immunofluorescence-based detection method.
Enveloped Viruses
HIV-1 ND 3.6 ≥6.4 ≥10.0
BVDV ND 2.4 ≥8.9 ≥11.3
PRV 1.6 3.7 4.6 9.9
WNV ND ND ≥7.8 NA
Non-Enveloped Viruses
HAV 1.5 2.4 4.2 8.1
CPV 1.5 3.4 1.1 6.0
B19V ND ND ≥3.9* NA
12CLINICAL PHARMACOLOGY
12.1Mechanism of Action
The active components of Humate-P consist of two different noncovalently bound proteins (FVIII and VWF). FVIII is an essential cofactor in activation of factor X, leading ultimately to the formation of thrombin and, subsequently, fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; activated platelets interact with clotting proteins to form a clot. VWF also serves as a stabilizing carrier protein for the procoagulant protein FVIII.7,8 The activity of VWF is measured as VWF:RCo.
12.3Pharmacokinetics
Hemophilia A
After infusion of Humate-P, a rapid increase of plasma FVIII:C is followed by a rapid decrease in activity and, subsequently, a slower rate of decrease in activity. Studies with Humate-P in subjects with hemophilia A have demonstrated a mean half-life of 12.2 (range: 8.4 to 17.4) hours.
VWD
The pharmacokinetics of Humate-P were studied in 41 subjects in a US study and in 28 subjects in a European study (see Clinical Studies [14.2]). In both studies, subjects were eva luated in the nonbleeding state prior to a surgical procedure. Table 8 summarizes the pharmacokinetics of Humate-P based on these studies. Wide inter-subject variability was observed in pharmacokinetic values obtained from these studies.
Table 8: Pharmacokinetics of Humate-P in Two Studies of Subjects in the Non-Bleeding State Prior to Surgery US Study European Study
IU = International Units.
BW = body weight.
*
Excluding 5 subjects with a half-life exceeding the blood sampling time of 24 or 48 hours.
†
Excluding 1 subject with a half-life exceeding the blood sampling time of 48 hours.
Number of subjects
Type 1 VWD
Type 2A VWD
Type 2B VWD
Type 2M VWD
Type 3 VWD 41
16
2
4
6
13 28
10
10
--
1
7
Dosage of Humate-P 60 IU VWF:RCo/kg BW 80 IU VWF:RCo/kg BW
Medi |
