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Gamunex

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Gamunex

CLINICAL PHARMACOLOGY

Mechanism of Action

Treatment of Primary Humoral Immunodeficiency

GAMUNEX (immune globulin intravenous (human) 10%) supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins. The mechanism of action in PI has not been fully elucidated.

Treatment of Idiopathic Thrombocytopenic Purpura

The mechanism of action of high doses of immunoglobulins in the treatment of Idiopathic Thrombocytopenic Purpura (ITP) has not been fully elucidated.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

The precise mechanism of action in CIDP has not been fully elucidated.

Pharmacokinetics

Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) to GAMIMUNE N 10%, Immune Globulin Intravenous (Human), 10%, (study 100152) and the other trial compared the pharmacokinetics of GAMUNEX (immune globulin intravenous (human) 10%) (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 (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) 10% to a 5% concentration of GAMUNEX (immune globulin intravenous (human) 10%) . [3, 4]

The main pharmacokinetic parameters of GAMUNEX (immune globulin intravenous (human) 10%) , measured as total IgG in study 100152 are displayed below:

Table 13: PK Parameters of GAMUNEX (immune globulin intravenous (human) 10%) and GAMIMUNE N 10% (Study 100152)

  GAMUNEX GAMIMUNEN 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)norma (kg*hr/mL) 17 16.51 1.83 16.95 17 16.69 2.04 16.99
T1/2b (days) 16 35.74 8.69 33.09 16 34.27 9.28 31.88
aPartial AUC: defined as pre-dose concentration to the last concentration common across both treatment periods in the same patient.
bonly 15 subjects were valid for the analysis of T1/2

The two pharmacokinetic trials with GAMUNEX (immune globulin intravenous (human) 10%) 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 days [3, 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 (immune globulin intravenous (human) 10%) treatment group and 8.2 +/- 2.0 mg/mL for the GAMIMUNE N, 10% control group [1].

Clinical Studies

Treatment of Primary Immunodeficiency

In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies (study 100175) GAMUNEX (immune globulin intravenous (human) 10%) 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 endpoint was the proportion of subjects with at least one of the following validated infections: pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

Table 14: Primary Endpoint Per Protocol Analysis (Study 100175)

  GAMUNE (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 4 (5%) 10 (14%)    
Exacerbati on of Chronic 5 (7%) 6 (8%)    
Sinusitis Pneumonia 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 (immune globulin intravenous (human) 10%) 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]

Treatment of Idiopathic Thrombocytopenic Purpura

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX (immune globulin intravenous (human) 10%) was at least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 x109/L to more than 50 x109/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 (immune globulin intravenous (human) 10%) 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]

Table 15: 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 (immune globulin intravenous (human) 10%) in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX (immune globulin intravenous (human) 10%) 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).

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

A multi-center, randomized, double-blind, Placebo-controlled trial (study 100538, The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX (immune globulin intravenous (human) 10%) .[43] This study included two separately randomized periods to assess whether GAMUNEX (immune globulin intravenous (human) 10%) was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy Period for up to 24 weeks) and whether long-term administration of GAMUNEX (immune globulin intravenous (human) 10%) could maintain long-term benefit (assessed in the 24 week Randomized Withdrawal Period).

In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule as in the Efficacy period. Any subject who was rescued (crossed over) and did not improve and maintain this improvement was withdrawn from the study.

Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMUNEX (immune globulin intravenous (human) 10%) or Placebo. Any subject who relapsed was withdrawn from the study.

The Efficacy Period and the Rescue treatment started with a loading dose of 2 g/kg bw of GAMUNEX (immune globulin intravenous (human) 10%) or equal volume of Placebo given over 2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses of 1 g/kg bw (or equivalent volume of Placebo) every three weeks.

The Responder rates of the GAMUNEX (immune globulin intravenous (human) 10%) and Placebo treatment groups as measured by the INCAT score. The INCAT (Inflammatory Neuropathy Cause and Treatment) scale is used to assess functional disability of both upper and lower extremities in demyelinating polyneuropathy. The INCAT scale has upper and lower extremity components (maximum of 5 points for upper (arm disability) and maximum of 5 points for lower (leg disability)) that add up to a maximum of 10-points (0 is normal and 10 is severely incapacitated). [44] At the start of the efficacy portion of the study, the INCAT scores were as follows: Upper Extremity mean was 2.2 ▒ 1.0, and median was 2.0 with a range of 0 to 5; Lower Extremity mean was 1.9 ▒ 0.9, and median was 2.0 with a range of 1 to 5; Total Overall Score mean was 4.2 ▒ 1.4, and median was 4.0 with a range of 2 to 9. A Responder was defined as a subject with at least 1-point improvement from baseline in the adjusted INCAT score that was maintained through 24 weeks.

Significantly more subjects with CIDP responded to GAMUNEX (immune globulin intravenous (human) 10%) : 28 of 59 subjects (47.5%) responded to GAMUNEX (immune globulin intravenous (human) 10%) compared with 13 of 58 subjects (22.4%) administered Placebo (25% difference; 95% CI 7%-43%]; p=0.006). The study included both subjects who were IGIV naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy with IGIV, as shown by the outcomes table, below.

Time to relapse for the subset of 57 subjects who previously responded to GAMUNEX (immune globulin intravenous (human) 10%) was evaluated: 31 were randomly reassigned to continue to receive GAMUNEX (immune globulin intravenous (human) 10%) and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMUNEX (immune globulin intravenous (human) 10%) experienced a significantly longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX (immune globulin intravenous (human) 10%) versus 45% with Placebo (hazard ratio, 0.19 [95% confidence interval, 0.05, 0.70]).

Table 16: Outcomes in Intent-to-Treat Population Efficacy Period

Efficacy Period GAMUNEX Placebo p-valuea
Responder Non-Responder Responder Non-Responder
All Subjects 28/59 (47.5%) 31/59 (52.5%) 13/58 (22.4%) 45/58 (77.6%) 0.006
IGIV Na´ve Subjects 17/39 (43.6%) 22/39 (56.4%) 13/46 (28.3%) 33/46 (71.7%) 0.174
IGIV Experienced Subjects 11/20 (55.0%) 9/20 (45.0%) 0/12 (0%) 12/12 (100%) 0.002
ap-value based on Fisher's exact method

The following table shows outcomes for the Rescue Phase (which are supportive data):

Table 17: Outcomes in Rescue Phase

Rescue Phase GAMUNEX Placebo p-valuea
Success Failure Success Failure
All Subjects 25/45
(55.6%)
20/45
(44.4%)
6/23
(26.1%)
17/23
(73.9%)
0.038
IGIV Na´ve Subjects 19/33(57. 6%) 14/33 (42.4%) 6/18
(33.3%)
12/18
(66.7%)
0.144
IGIV Experienced Subjects 6/12
(50%)
6/12
(50%)
0/5 (0%) 5/5
(100%)
0.102
ap-value based on Fisher's exact method

The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period:

Figure 1: Outcome for Randomized Withdrawal Period

Outcome for Randomized Withdrawal Period - Illustration

REFERENCES

1. Kelleher J, F.G., Cyrus P, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune Deficiency (PID), 2000. Report on file.

2. Data on File.

3. Bayever E, M.F., Sundaresan P, Collins S, Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999.

4. Lathia C, E.B., Sundaresan PR, Schwartz L, A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100174). 2000.

43. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized Placebo-controlled trial. Lancet Neurol 2008. 7:136-144.

44. Hughes R, Bensa S, Willison H, Van den BP, Comi G, Illa I, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001 Aug;50(2):195-201.

Last reviewed on RxList: 10/3/2008
This monograph has been modified to include the generic and brand name in many instances.

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