June 27, 2016
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Gamunex-C

CLINICAL PHARMACOLOGY

Mechanism Of Action

PI

GAMUNEX-C supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacterial, viral, parasitic, and mycoplasmal agents, and their toxins. The mechanism of action in PI has not been fully elucidated.

ITP

The mechanism of action of high doses of immunoglobulins in the treatment of ITP has not been fully elucidated.

CIDP

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

Pharmacodynamics

Immunoglobulins are fractionated blood products made from pooled human plasma. Immunoglobulins are endogenous proteins produced by B lymphocyte cells. The main component of GAMUNEX-C is IgG ( ≥ 98%) with a sub-class distribution of IgG1, IgG2, IgG3 and IgG4 of approximately 62.8%, 29.7%, 4.8% and 2.7% respectively.

Pharmacokinetics

Two pharmacokinetic crossover trials were carried out with GAMUNEX-C in 44 subjects with Primary Humoral Immunodeficiency to assess intravenous vs subcutaneous administration. In the first study, a single sequence, open-label, crossover trial in adults and adolescents, the pharmacokinetics, safety, and tolerability of SC administered GAMUNEX-C in subjects with PI were evaluated. A total of 32 and 26 subjects received GAMUNEX-C as IV or SC for PK study, respectively, of whom 3 were adolescents. Subjects received GAMUNEX-C 200-600 mg/kg IV every 3-4 weeks for at least 3 months, at which time they entered the IV phase of the study. Subjects were crossed over to weekly SC infusions. The weekly SC dose was determined by multiplying the total IV dose by 1.37 and dividing the resultant new total dose by 3 or 4 depending on the previous IV interval.

In the second study, a single sequence, open-label, crossover trial, the pharmacokinetics, safety, and tolerability of SC administered GAMUNEX-C were evaluated in children and adolescents. The design of the study was essentially the same as above. A total of 11 and 10 subjects (age 2 to 5 years, N=1; 6 to 11 years, N = 5 IV, 4 SC; 12-16 years: N = 5) received GAMUNEX-C as IV or SC for PK analysis, respectively.

Intravenous Administration

The pharmacokinetic parameters of GAMUNEX-C, measured as total IgG for intravenous administration are shown in Table 13.

Table 13: PK Parameters Following IV Administration of GAMUNEX®-C by Age

Age Group Statistics t½ (hr) AUC(0-t) (hr*mg/mL) AUC(0-tau) (hr*mg/mL) CL(0-t) (mL/hr/kg) Vss (mL/kg)
2 - 5 years Mean 1038.50 7479.0 7499.0 0.05430 82.040
N = 1 SD* NA* NA* NA* NA* NA*
6 - 11 years Mean 758.52 5953.6 6052.6 0.09128 94.784
N = 5 SD 137.989 1573.84 1333.59 0.027465 17.6773
12 - 16 years Mean 717.90 8131.9 8009.5 0.07029 73.303
N = 8 SD* 170.141 1173.38 1358.76 0.015912 17.2204
≥ 17 years 720.62 7564.9 7524.8 0.06243 65.494
N = 29 Mean * SD 130.864 1190.68 1183.05 0.015547 18.7172
* SD - standard deviation; NA - not applicable.
Source: studies 060001, T5004-401

PI: Subcutaneous Administration

The PK parameter (AUC of total IgG) following IV and SC administration is summarized in Table 14 for subcutaneous vs intravenous administration in the two pharmacokinetic trials. In the adult and adolescent trial, the lower bound of the 90% confidence interval for the geometric mean ratio of AUC (SC vs. IV) was 0.861, therefore, meeting the pre-specified non-inferiority margin between the two modes of administration. The PK analysis results in children and adolescents are consistent to those in the adult and adolescent trial, demonstrating the appropriateness of the conversion factor of 1.37 applied to calculating the SC dose from the IV dose of GAMUNEX-C in pediatric populations.

Table 14: Summary of AUC of Total IgG at Steady State Following IV or SC Administration of GAMUNEX®-C by Age

Route of Administration IV
(N = 43)
SC
(N = 36)
AUC Ratio, SC/IV
Age Group Statistics AUC0-τ,IV
(h*mg/mL)
(0-21 days)
AUC0-τ,IV
(h*mg/mL)
(0-28 days)
Adj._AUC0-τ,IV*
(h*mg/mL)
(0-7 days)
AUC0-τ,SC
(h*mg/mL)
(0-7 days)
2-5 years, N 1 1 1 1
  Mean N C† 7498.7 1874.7 2023.0 1.080
  %CV N C† N C† N C† NC† -
  Range NC† NC† NC† NC† NC†
6-11 years, N 5 5 4 4
  Mean 6052.7 NC† 2017.6 2389.2 1.135
  %CV 22% NC† 22% 19% -
  Range 4868 - 8308 NC† 1623 - 2769 1971 - 3039 1.10 - 1.21
12-16 years, N 5 3 8 7 7
  Mean 7396.0 9032.0 2387.6 2361.9 0.982
  %CV 17% 9% 15% 14% -
  Range 5271 - 8754 8504 - 9950 1757 - 2918 1876 - 2672 0.86 - 1.07
≥ 17years, N 10 19 29 24 24
  Mean 7424.7 7577.4 2094.5 1899.9 0.882
  %CV 14% 17% 20% 20% -
  Range 5781 - 9552 5616 -10400 1404 - 3184 1300 - 2758 0.70 - 1.04
* Adj._ AUC0-τ,IV: Adjusted weekly IV AUC(0-7 days) is calculated as AUC(0-21 days)/3 or AUC(0-28 days)/4.
† NC - not calculated
Source: Studies 060001, T5004-401

The mean trough concentrations (mean Ctrough) of total IgG following IV and SC administration are presented in Table 15 for both studies.

Table 15: Mean Trough Concentrations of Total IgG (mg/mL)

  Adult, Adolescent* Child, Adolescent†
IV Mean Ctrough SC Mean Ctrough IV Mean Ctrough SC Mean Ctrough
n 32 28 11 10
Mean (mg/mL) 9.58 11.4 9.97 13.25
%CV 22.3 20.4 19 14
Range 6.66-14.0 8.10-16.2 7.84-13.20 10.77-16.90
* Measured in plasma; † Measured in serum

In contrast to plasma total IgG levels observed with monthly IV GAMUNEX-C treatment (rapid peaks followed by a slow decline), the plasma IgG levels in subjects receiving weekly SC GAMUNEX-C therapy were relatively stable (Figure 7, adult and adolescent trial).

Figure 7: Mean Steady-state Plasma Total IgG Concentration vs. Time Curves Following IV Administration or Weekly SC Administration in Adult and Adolescents

Mean Steady-state Plasma Total IgG Concentration vs. Time Curves -  Illustration

Clinical Studies

PI: Intravenous Administration

In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies GAMUNEX-C was demonstrated to be at least as efficacious as GAMIMUNE N, 10% 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.(23) Twenty-six subjects were excluded from the Per Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The analysis for efficacy was based on the annual rate of bacterial infections, pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

Table 16: Efficacy Results Per Protocol Analysis

  No. of Subjects with at Least One Infection (%) Mean Difference (90% Confidence Interval) p-Value
GAMUNEX®-C
(n=73)
GAMIMUNE® N, 10%
(n=73)
Validated Infections 9 (12%) 17 (23%) -0.117 (-0.220, -0.015) 0.06
Acute Sinusitis 4 (5%) 10 (14%)    
Exacerbation of Chronic Sinusitis 5 (7%) 6 (8%)    
Pneumonia 0 (0%) 2 (3%)    
Any Infection* 56 (77%) 57 (78%) -0.020 (-0.135, 0.096) 0.78
* Validated infections plus clinically defined, non-validated infections.

The annual rate of validated infections (Number of Infections/year/subject) was 0.18 in the group treated with GAMUNEX-C 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).

ITP

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to test the hypothesis that GAMUNEX-C 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. Twenty-four percent of the subjects were less than or equal to 16 years of age.(25)

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

Table 17: Platelet Response of Per Protocol Analysis

  Number of Responders (percent of all subjects) Mean Difference (90% Confidence Interval)
GAMUNEX®-C
(n=39)
GAMIMUNE® N, 10%
(n=42)
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-C in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX-C 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).

CIDP

A multi-center, randomized, double-blind, Placebo-controlled trial (The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX-C.(26) This study included two separately randomized periods to assess whether GAMUNEX-C 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-C 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-C 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 body weight of GAMUNEX-C 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 body weight (or equivalent volume of Placebo) every three weeks.

The Responder rates of the GAMUNEX-C and Placebo treatment groups was 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).(27) 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.

More subjects with CIDP responded to GAMUNEX-C: 28 of 59 subjects (47.5%) responded to GAMUNEX-C 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 na´ve 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-C was evaluated: 31 were randomly reassigned to continue to receive GAMUNEX-C and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMUNEX-C experienced a longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX-C versus 45% with Placebo (hazard ratio, 0.19; 95% confidence interval, 0.05, 0.70).

Table 18: Outcomes in Intent-to-Treat Population Efficacy Period

Efficacy Period GAMUNEX®-C Placebo p- * value
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 - Naive 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
* p-value based on Fisher's exact method

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

Table 19: Outcomes in Rescue Phase

Rescue Phase GAMUNEX®-C Placebo p-value*
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 - Naive 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
* p-value based on Fisher's exact method

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

Figure 8: Outcome for Randomized Withdrawal Period

Outcome for Randomized Withdrawal Period Illustration

REFERENCES

23. Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial. Internat Immunopharmacol 2003;3:1325–33.

24. Wasserman RL, Irani A-M, Tracy J, et al. Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease. Clinical and Experimental Immunology 2011;161:518-26.

25. Bussell JB, Eldor A, Kelton JG, et al. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action and impact on quality of life. Thromb Haemost 2004;91:771–8.

26. 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 randomised placebo-controlled trial. Lancet Neurol 2008;7:136-44.

27. Hughes R, Bensa S, Willison H, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001;50(2):195-201.

Last reviewed on RxList: 4/5/2016
This monograph has been modified to include the generic and brand name in many instances.

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