CLINICAL PHARMACOLOGY
Antihemophilic factor (AHF) is a protein found in normal plasma which is necessary for clot formation.
The administration of HEMOFIL M AHF provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect of patients with hemophilia A (classical hemophilia). The administration of HEMOFIL M AHF will also correct deficiencies caused by circulating inhibitors when the inhibitor level does not exceed 10 Bethesda Units per mL.
The half-life of HEMOFIL M, Antihemophilic Factor (Human) (AHF), Method M, Monoclonal Purified, administered to Factor VIII deficient patients has been shown to be 14.8 ± 3.0 hours.
Use of an organic solvent (tri-n-butyl phosphate; TNBP) in the manufacture of Antihemophilic Factor (Human) has little or no effect on AHF activity, while lipid enveloped viruses, such as hepatitis B and human immunodeficiency virus (HIV) are inactivated. 1 Prince, et al, report inactivation of at least 10,000 Chimpanzee Infectious Doses (CID-50) of hepatitis B virus, 10,000 CID-50 of hepatitis non A, non B virus, and 30,000 Tissue Culture Infectious Doses of HIV with TNBP/detergent treatment during manufacture of an Antihemophilic Factor (Human) concentrate. 2 In vitro studies demonstrate that the HEMOFIL M AHF, manufacturing process provides for significant viral reduction. These studies, summarized in Table 1, demonstrate virus clearance during the HEMOFIL M AHF manufacturing process using human immunodeficiency virus, Type 1 (HIV-1); bovine viral diarrhea virus (BVD), a model for lipid enveloped RNA viruses, such as hepatitis C virus (HCV); pseudorabies virus (PRV), a model for lipid enveloped DNA viruses, such as herpes; porcine parvovirus (PPV), a model for non-lipid enveloped DNA viruses, such as human parvovirus B19; and hepatitis A virus (HAV), a model for non-lipid enveloped RNA viruses. These reductions are achieved through a combination of process chemistry, partitioning and/or inactivation during solvent/detergent treatment, immunoaffinity chromatography, Q-Sepharose column chromatography and lyophilization.
Table 1
In Vitro Virus Clearance During the Manufacture of HEMOFIL M AHF
|
Process Step Evaluated
|
Virus Clearance, log10 |
|
Lipid-enveloped
|
Non-Lipid enveloped
|
|
HIV-1
|
BVD
|
PRV
|
PPV
|
HAV
|
|
Solvent/Detergent Treatment
|
10.3
|
3.8
|
4.3
|
* |
* |
|
Immunoaffinity Chromatography
|
N.A. ** |
N.A. ** |
N.A. ** |
4.2
|
5.3
|
|
Q-Sepharose Column Chromatography
|
N.T. **/* |
2.3
|
1.1
|
1.4
|
<0.9 **/** |
|
Lyophilization
|
N.T. **/* |
N.T. **/* |
N.T. **/* |
N.T. **/* |
1.9
|
| Cumulative Total, log10 |
10.3 |
6.1 |
5.4 |
5.6 |
7.3 |
|
*Solvent/Detergent treatment inactivates only lipid enveloped viruses. PPV and HAV are non-lipid enveloped viruses. |
|
**Not Applicable for lipid enveloped viruses due to the presence of solvent/detergent in the starting material.
|
|
**/* Not Tested. |
|
**/** Value not included in cumulative total. |
|
HEMOFIL M AHF was administered to 11 patients previously untreated with Antihemophilic Factor (Human). They have shown no signs of hepatitis or HIV infection following three to nine months of evaluation.
A study of 25 patients treated with HEMOFIL M AHF, and monitored for three to six months has demonstrated no evidence of antibody response to mouse protein. More than 1,000 infusions of HEMOFIL M AHF have been administered during the clinical trials with no significant reactions. Reported events included a single episode each of chest tightness, fuzziness and dizziness, and one patient reported an unusual taste after each infusion.
|
