Gamunex (Immune Globulin Intravenous Human) - Clinical Pharmacology

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.

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:

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

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:

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 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® 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 action^5-10.

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

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.