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Gamunex (Immune Globulin Intravenous Human) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, (GAMUNEX®) is a ready-to-use sterile solution of human immune globulin protein for intravenous administration. GAMUNEX® consists of 9%-11% protein in 0.16-0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. GAMUNEX® contains trace levels of fragments and IgA (average 0.046 mg/mL). IgM levels were at or below the limit of quantitation (0.002 g/L). The distribution of IgG subclasses is similar to that found in normal serum. The measured buffer capacity is 35 mEq/L and the osmolality is 258 mOsmol/kg solvent, which is close to physiological osmolality (285-295 mOsmol/kg). The pH of GAMUNEX® is 4.0-4.5. GAMUNEX® contains no preservative.

GAMUNEX® is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography. Two of the four ethanol fractionation steps of the Cohn-Oncley process have been replaced by tandem anion-exchange chromatography. The IgG proteins are not subjected to heating or chemical or enzymatic modification steps. Fc and Fab functions of the IgG molecule are retained, but do not activate complement or pre-Kallikrein activity in an unspecific manner. The protein is stabilized during the process by adjusting the pH of the solution to 4.0-4.5. Isotonicity is achieved by the addition of glycine. GAMUNEX® is incubated in the final container (at the low pH of 4.0-4.3), for a minimum of 21 days at 23° to 27°C. The product is intended for intravenous administration.

The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: human immunodeficiency virus, type I (HIV-1) as the relevant virus for HIV-1 and HIV-2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for large DNA viruses (e.g. herpes viruses); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant non-enveloped virus, and porcine parvovirus (PPV) as a model for human parvovirus B19.

The following process steps contribute to virus inactivation and/or removal: caprylate precipitation/cloth filtration, caprylate incubation, column chromatography and final container low pH incubation. Caprylate is the basis of two mechanistically distinct virus clearance steps, the caprylate precipitation/cloth filtration step and the caprylate incubation step. During the caprylate precipitation/cloth filtration step, protein impurities and potential enveloped or non-enveloped viral contaminants are precipitated by caprylate and the precipitate is removed from the product stream by filtration through a cloth filter. In a subsequent step, enveloped viruses are inactivated during incubation with caprylate. The table below presents the contribution of each process step to virus reduction and the overall process reduction. Virus removal steps were evaluated independently and in combination to identify those steps, which were mechanistically distinct. Overall virus reduction was calculated only from steps that were mechanistically independent from each other and truly additive. In addition, each step was verified to provide robust virus reduction across the production range for key operating parameters.

Log10 Virus Reduction
Process Step Enveloped Viruses Non-enveloped Viruses
HIV PRV BVDV Reo HAV PPV
Caprylate Precipitation/Cloth Filtration C/I a C/I 2.4 ± 0.3 2.1 ± 0.4 2.6 ± 0.2 2.2 ± 0.1
Caprylate Incubation >/= 4.5 >/= 4.6 >/= 4.5 NA b NA NA
Depth Filtration d CAP c CAP CAP >/= 4.3 >/= 2.0 3.3 ± 0.3
Column Chromatography >/= 3.0 >/= 3.3 4.0 ± 0.3 >/= 4.0 >/= 1.4 4.2 ± 0.2
Low pH Incubation (21 days) >/= 6.5 >/= 4.3 3.5 ± 0.4 NA NA NA
Global Reduction >/= 14.0 >/= 12.2 >/= 14.4 >/= 6.1 >/= 4.0 6.4
a C/I -- Interference by caprylate precluded determination of virus reduction for this step. Although removal of viruses is likely to occur at the caprylate precipitation/cloth filtration step, BVDV is the only enveloped virus for which reduction is claimed. The presence of caprylate prevents detection of other, less resistant enveloped viruses and therefore their removal cannot be assessed.
b Not Applicable -- This step has no effect on non-enveloped viruses.
c CAP -- The presence of caprylate in the process at this step prevents detection of enveloped viruses, and their removal cannot be assessed.
d Some mechanistic overlap occurs between depth filtration and other steps. Therefore, Bayer has chosen to exclude this step from the global virus reduction calculations.

CLINICAL PHARMACOLOGY

PRIMARY HUMORAL IMMUNODEFICIENCY (PI)

In a double-blind, randomized, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies (study 100175) GAMUNEX®, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, was demonstrated to be at least as efficacious as GAMIMUNE® N, Immune Globulin Intravenous (Human), in the prevention of any infection, i.e. validated plus clinically defined, non-validated infections of any organ system, during a nine month treatment period. Twenty six subjects were excluded from the Per Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The primary efficacy endpoint was the proportion of subjects with at least one of the following validated infections: pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

Primary Endpoint Per Protocol Analysis (Study 100175)
GAMUNEX®
(n = 73)
No. of subjects with
at least one infection
GAMIMUNE® N
(n = 73)
No. of subjects with
at least one infection
Mean Difference
(90% confidence interval)
p-Value
Validated Infections 9 (12%) 17 (23%) -0.117
(-0.220, -0.015)
0.06
Acute Sinusitis Exacerbation of Chronic Sinusitis Pneumonia 4 (5%) 10 (14%)
5 (7%) 6 (8%)
0 (0%) 2 (3%)
Any Infection (Validated plus Clinically defined non-validated Infections) 56 (77%) 57 (78%) -0.020
(-0.135, 0.096)
0.78

The annual rate of validated infections (Number of Infection/year/subject) was 0.18 in the group treated with GAMUNEX® and 0.43 in the group treated with GAMIMUNE® N, 10% (p=0.023). The annual rates for any infection (validated plus clinically-defined, non-validated infections of any organ system) were 2.88 and 3.38, respectively (p=0.300). 1, 2

A post hoc analysis of serious infection events during the trial showed five (5) cases of clinically defined pneumonia occurred in 4 GAMUNEX® treated subjects and 11 cases of validated or clinically defined pneumonia occurred in 9 GAMIMUNE® N 10% treated subjects and 1 case of sepsis occurred in a GAMIMUNE® N 10% treated subject. The annual infection rate and 98% confidence interval for serious infections are:

Post Hoc Analysis of Serious Infections * (Study 100175)
GAMUNEX®
(n = 73)
Annual Infection Rate
(Infections/year/subject);
98% Confidence Interval
GAMIMUNE® N
(n = 73)
Annual Infection Rate
(Infections/year/subject);
98% Confidence Interval
Serious Infections (Validated and clinically defined Pneumonia, Sepsis) 0.07 (0 1 -0.16) 0.18 (0.06-0.32)
*The definition of Serious Infections was any of the following: validated plus clinically-defined, non-validated pneumonia, bacteremia/sepsis, osteomyelitis/septic arthritis, visceral abscess, bacterial and/or viral meningitis; however, only pneumonia and sepsis were observed.
1 The actual lower limit was less than 0, but this is not a plausible value.

As a secondary endpoint, consequences of infections were recorded and are displayed in the table below:

Secondary Endpoint Clinical Outcomes (Study 100175)
GAMUNEX®
No. of patient days on study:
21479
GAMIMUNE® N
No. of patient days on study:
21388
Days on prophylactic antibiotics 3078 (14.4%) 4305 (20.1%)
Days on therapeutic antibiotics 2157 (10.0%) 2494 (11.7%)
Days off school/work 240 (1.1%) 230 (1.1%)
Days with visits of physician's
office or emergency room
148 (0.7%) 174 (0.8%)
Hospitalization days 38 (0.2%) 71 (0.3%)


Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX®, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, in 38 subjects with Primary Humoral Immunodeficiencies given 3 infusions 3 or 4 weeks apart of test product at a dose of 100-600 mg/kg body weight per infusion. One trial compared the pharmacokinetic characteristics of GAMUNEX® to Gamimune N 10%, Immune Globulin Intravenous (Human), 10% (study 100152) and the other trial compared the pharmacokinetics of GAMUNEX® (10% strength) with a 5% concentration of this product (study 100174). The ratio of the geometric least square means for dose-normalized IgG peak levels of GAMUNEX® and GAMIMUNE® N was 0.996. The corresponding value for the dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK parameters were within the pre-established limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX® 10% to a 5% concentration of GAMUNEX®. 3, 4

The main pharmacokinetic parameters of GAMUNEX®, measured as total IgG in study 100152 are displayed below:

PK Parameters of GAMUNEX® and GAMIMUNE® N 10% (Study 100152)
GAMUNEX® GAMIMUNE® N 10%
N Mean SD Median N Mean SD Median
Cmax
(mg/mL)
17 19.04 3.06 19.71 17 19.31 4.17 19.30
Cmax-norm
(kg/mL)
17 0.047 0.007 0.046 17 0.047 0.008 0.047
AUC(0-tn) a
(mg *hr/mL)
17 6746.48 1348.13 6949.47 17 6854.17 1425.08 7119.86
AUC(0-tn)norm a
(kg *hr/mL)
17 16.51 1.83 16.95 17 16.69 2.04 16.99
T1/2 b
(days)
16 35.74 8.69 33.09 16 34.27 9.28 31.88
a Partial AUC: defined as pre-dose concentration to the last concentration common across both treatment periods in the same patient.
b only 15 subjects were valid for the analysis of T1/2

The two pharmacokinetic trials with GAMUNEX® show the IgG concentration/time curve follows a biphasic slope with a distribution phase of about 5 days characterized by a fall in serum IgG levels to about 65-75% of the peak levels achieved immediately post-infusion. This phase is followed by the elimination phase with a half-life of approximately 35 days3,4. IgG trough levels were measured over nine months in the therapeutic equivalence trial (100175). Mean trough levels were 7.8 +/- 1.9 mg/mL for the GAMUNEX® treatment group and 8.2 +/- 2.0 mg/mL for the GAMIMUNE® N, 10% control group1.

IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)

The mechanism of action of high doses of immunoglobulins in the treatment of Idiopathic Thrombocytopenic Purpura (ITP) has not been fully elucidated. Several lines of evidence suggest that Fc-receptor blockade of phagocytes as well as down regulation of auto-reactive B-cells by antiidiotypic antibodies provided by IGIV may constitute the main mechanisms of action5-10.

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX® was at least as effective as GAMIMUNE® N, 10% in raising platelet counts from less than or equal to 20 × 109/L to more than 50 × 109/L within 7 days after treatment with 2 g/kg IGIV (study 100176). Twenty-four percent of the subjects were less than or equal to 16 years of age.

GAMUNEX® was demonstrated to be at least as effective as GAMIMUNE® N, 10% in the treatment of adults and children with acute or chronic ITP. 11

Platelet Response of Per Protocol Analysis (Study 100176)
     GAMUNEX®
(n = 39)
GAMIMUNE® N
(n = 42)
Mean Difference
(90% confidence interval)
By Day 7 35 (90%) 35 (83%) 0.075
(-0.037, 0.186)
By Day 23 35 (90%) 36 (86%) 0.051
(-0.058, 0.160)
Sustained for 7 days 29 (74%) 25 (60%) 0.164
(0.003, 0.330)

A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX® in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX® on three occasions for treatment of relapses. The infusion rate was randomly assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability was not permitted. Pre-treatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this was at the lowest dose rate level (0.08 mL/kg/min).

GENERAL

GAMUNEX®, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins, which were demonstrated to be effective in the prevention or attenuation of lethal infections in animal models. GAMUNEX® proved to be effective in preventing severe infections in patients with Primary Humoral Immunodeficiency (PI).

Glycine (aminoacetic acid) is a nonessential amino acid normally present in the body. Glycine is a major ingredient in amino acid solutions employed in intravenous alimentation12. While toxic effects of glycine administration have been reported13, the doses and rates of administration were 3-4 fold greater than those for GAMUNEX®. In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects14. GAMUNEX® doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. 0.2M Glycine stabilizer has been used safely in GAMIMUNE® N since 1992.

Caprylate is a saturated medium-chain (C8) fatty acid of plant origin, which is subjected to rapid beta-oxidation. Medium chain fatty acids are considered to be essentially non-toxic. Human subjects receiving medium chain fatty acids parenterally have tolerated doses of 3.0 to 9.0 g/kg/day for periods of several months without adverse effects15. Residual Caprylate concentrations in the final container are no more than 0.216 g/L (1.3 mmol/L).

The buffering capacity of GAMUNEX® is 35.0 mEq/L(0.35 mEq/g protein). A dose of 1000 mg/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45-50 mEq/L of blood, or 3.6 mEq/kg body weight16. Thus, the acid load delivered with a dose of 1000 mg/kg of GAMUNEX® would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.

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