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Carimune NF (Immune Globulin Intravenous (Human)) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Immune Globulin Intravenous (Human) (IGIV), Carimune™ NF Nanofiltered, is a sterile, highly purified polyvalent antibody product containing in concentrated form all the IgG antibodies which regularly occur in the donor population (1). This immunoglobulin preparation is produced by cold alcohol fractionation from the plasma of US donors. Part of the fractionation may be performed by another US-licensed manufacturer. Carimune™ NF is made suitable for intravenous use by treatment at acid pH in the presence of trace amounts of pepsin (2,3). The manufacturing process by which Carimune™ NF is prepared from plasma consists of fractionation and purification steps that comprise filtrations in the presence of filter aids. Four of these steps were validated for virus elimination of both enveloped and non-enveloped viruses. To complement the existing virus elimination / inactivation mechanism in the Carimune™ NF manufacturing process, nanofiltration (removing viruses via size-exclusion) was introduced as an additional virus removal step into the manufacturing process (4,5). Nanofiltration is performed prior to the viral inactivation step (pH 4 in presence of pepsin) in order to reduce the potential viral load before inactivation is performed. Treatment with pepsin at pH4 rapidly inactivates enveloped viruses (6).

The Carimune™ NF manufacturing process provides a significant viral reduction in in vivo studies. These studies results are summarized in Table 1, demonstrate virus clearance during Carimune™ NF manufacturing using model viruses for lipid enveloped and non-enveloped viruses. The LRFs (log10 reduction factors) from nanofiltration, and viral elimination and inactivation steps were:

Table 1
Viral Elimination and Inactivation
Virus HIV BVDV PRV SFV SV BEV
Genome RNA RNA DNA RNA RNA RNA
Envelope Yes Yes Yes Yes Yes No
Size (nm) 80-100 40-60 120-200 50-70 50-70 28-30
Fractionation&
Depth filtration
15.5 nt 16.0 9.3 12.4 14.1
pH 4 / pepsin > 6.1 > 4.4 > 5.3 > 6.8 nt nt
Nanofiltration > 4.9 > 4.5 > 4.4 nt > 7.5 > 5.1
Overall reduction > 26 > 9 > 25 > 16 > 19 > 19
HIV: Human immunodeficiency virus, model for HIV 1 and HIV 2
BVDV: Bovine viral diarrhea virus, model for HCV (Hepatitis C virus)
PRV: Pseudorabies virus, model for large, enveloped DNA viruses (e,g., herpes virus)
SFV: Semliki Forest virus, model for HCV
SV: Sindbis virus, model for HCV
BEV: Bovine enterovirus, model for HAV (Hepatitis A virus)
Nt: not tested
PRV and the two model viruses for HCV, BVDV and SFV, were inactivated within 1/10, and HIV within 1/2 of the incubation time (pH 4/pepsin treatment) used during production of Carimune™ NF.

The preparation contains at least 96% of IgG and after reconstitution with a neutral unbuffered diluent has a pH of 6.6 ± 0.2. Most of the immunoglobulins are monomeric (7 S) IgG; the remainder consists of dimeric IgG and a small amount of polymeric IgG, traces of IgA and IgM and immunoglobulin fragments (7). The distribution of the IgG subclasses corresponds to that of normal serum (8,9,10,11). Final container lyophilized units are prepared so as to contain 1, 3, 6, or 12 g protein with 1.67 g sucrose and less than 20 mg NaCl per gram of protein. The lyophilized preparation contains no preservative and may be reconstituted with sterile water, 5% dextrose or 0.9% saline to a solution with protein concentrations ranging from 3% to 12% (see Table 3). The patient's fluid, electrolyte, caloric requirements and renal function should be considered in selecting an appropriate diluent and concentration.

Table 2 Calculated Carimune™ NF Osmolality (mOsm/kg)
Concentration
Diluent 3% 6% 9% 12%
0.9% NaCl 498 690 882 1074
5% Dextrose 444 636 828 1020
Sterile Water 192 384 576 768

CLINICAL PHARMACOLOGY

Carimune™ NF Nanofiltered contains a broad spectrum of antibody specificities against bacterial, viral, parasitic, and mycoplasma antigens, that are capable of both opsonization and neutralization of microbes and toxins. The 3 week half-life of Immune Globulin Intravenous (Human), Carimune™ NF, corresponds to that of Immune Globulin (Human) for intramuscular use, although individual variations in half-life have been observed (12,13). Appropriate doses of Carimune™ NF restore abnormally low immunoglobulin G levels to the normal range. One hundred percent of the infused dose of IGIV-products is available in the recipient's circulation immediately after infusion. After approximately 6 days, equilibrium is reached between the intra- and extravascular compartments, with immunoglobulin G being distributed approximately 50% intravascular and 50% extravascular. In comparison, after the intramuscular injection of immune globulin, the IgG requires 2-5 days to reach its maximum concentration in the intravascular compartment. This concentration corresponds to about 40% of the injected dose (13).

While Carimune™ NF has been shown to be effective in some cases of Immune Thrombocytopenic Purpura (ITP) (see INDICATIONS AND USAGE), the mechanism of action in ITP has not been fully elucidated. Toxicity from overdose has not been observed on regimens of 0.4 g/kg body weight each day for 5 days (14,15,16). Sucrose is added to Carimune™ NF for reasons of stability and solubility. Since sucrose is excreted unchanged in the urine when given intravenously, Carimune™ NF, may be given to diabetics without compensatory changes in insulin dosage regimen. Please see WARNINGS section.

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