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Vivaglobin

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Vivaglobin

CLINICAL PHARMACOLOGY

Vivaglobin® (immune globulin subcutaneous (human)) Immune Globulin Subcutaneous (Human), supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents.

Vivaglobin® (immune globulin subcutaneous (human)) is to be administered by injection into the subcutaneous tissue. Subcutaneous administration of immune globulin decreases bioavailability compared to intravenous administration.1 The bioavailability of Vivaglobin® (immune globulin subcutaneous (human)) is approximately 73% compared to immune globulin intravenous (IGIV). Various factors, such as the site of administration and IgG catabolism, can affect absorption.1,2 With Vivaglobin® (immune globulin subcutaneous (human)) administration, peak serum IgG levels are lower than those achieved with IGIV. Subcutaneous administration results in relatively stable steady-state serum IgG levels when administered on a weekly basis.2,3 This serum IgG profile is representative of that seen in a normal population.

The pharmacokinetics (PK) of Vivaglobin® (immune globulin subcutaneous (human)) was evaluated in the PK phase of a pivotal 12-month clinical study conducted in the United States and Canada in subjects with primary immune deficiency (PID) (see Clinical Studies). Subjects who were previously treated with IGIV were switched over to weekly Vivaglobin® (immune globulin subcutaneous (human)) subcutaneous treatment and, after a 3-month wash-in/wash-out period, doses were individually adjusted to provide an IgG systemic exposure (area under the curve; AUC) that was not inferior to the AUC of the previous weekly-equivalent IGIV dose. For the 19 per-protocol subjects completing the wash-in/wash-out period, the average Vivaglobin® (immune globulin subcutaneous (human)) dose adjustment was 137% (range: 103 to 192%) of the previous weekly-equivalent IGIV dose. Following 10 to 12 weeks of treatment with Vivaglobin® (immune globulin subcutaneous (human)) at this adjusted dose, the final steady-state AUC determinations were made. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Vivaglobin® (immune globulin subcutaneous (human)) versus IGIV treatment was 94.5% (range: 71.4 to 110.1%) with a lower 95% confidence limit of 89.8% for the per-protocol population (n = 17). Table 2 summarizes additional pharmacokinetic parameters for this study including dosing and serum IgG peak and trough levels following treatment with IGIV and Vivaglobin® (immune globulin subcutaneous (human)) .

Table 2: Summary of Additional Pharmacokinetic Parameters – US and Canada PK Sub-study – Per-protocol Subjects

  IGIV Vivaglobin®
Number of Subjects 17 17
Dose*
  Mean 120 mg/kg 165 mg/kg
  Range 55 – 243 mg/kg 63 – 319 mg/kg
IgG peak levels
  Mean 1735 mg/dL 1163 mg/dL
  Range 1110 – 3230 mg/dL 743 – 2240 mg/dL
IgG trough levels
  Mean 883 mg/dL 1064 mg/dL
  Range 430 – 1600 mg/dL 547 – 2140 mg/dL
*For IGIV: weekly-equivalent dose, Standardized to a 7-day period

A non-IND 6-month clinical study was conducted in Europe and Brazil in 60 subjects with PID. After the subjects had reached steady state with weekly Vivaglobin® (immune globulin subcutaneous (human)) administration, peak serum IgG levels were observed after a mean of 2.5 days (range 0 to 7 days) in 41 subjects.

In contrast to serum IgG levels observed with monthly IGIV treatment (rapid peaks followed by a slow decline), the serum IgG levels in subjects receiving weekly subcutaneous Vivaglobin® (immune globulin subcutaneous (human)) therapy were relatively stable in both studies.

Clinical Studies

The pivotal open-label, prospective, multicenter clinical study conducted in the United States and Canada evaluated the pharmacokinetics, efficacy, safety and tolerability of Vivaglobin® Immune Globulin Subcutaneous (Human), in adult and pediatric subjects with primary immune deficiency (PID). In this study, 65 adult and pediatric PID subjects previously treated monthly with IGIV were switched to weekly subcutaneous administrations of Vivaglobin® (immune globulin subcutaneous (human)) for 12 months. The per-protocol efficacy analysis included 51 subjects. Subjects received a weekly mean Vivaglobin® (immune globulin subcutaneous (human)) dose of 158 mg/kg body weight (range: 34 to 352 mg/kg), which was 136% (range: 99 to 188%) of their previous weekly-equivalent IGIV dose.

The annual rate of serious bacterial infections (defined as bacterial pneumonia, meningitis, sepsis, osteomyelitis, and visceral abscesses), the primary endpoint, was 0.04 infections per subject per year (one-sided upper 99% confidence interval: 0.14) for the per-protocol set (n = 51). Pneumonia was reported in two subjects. The annual rate of any infections, a secondary endpoint, was 4.4 infections per subject per year.

The IgG subclass levels observed in this study were consistent with a physiologic distribution pattern (mean values) IgG1: 703 mg/dL, IgG2: 278 mg/dL, IgG3: 36 mg/dL, and IgG4: 30 mg/dL.

Table 3 summarizes the dosing and annual rate of infections for the efficacy phase of this study.

Table 3: Dose and Annual Rate of Infections with Vivaglobin® (immune globulin subcutaneous (human)) – Per-protocol Subjects Efficacy Phase of the US and Canada Study

Number of Subjects (Efficacy) 51
Vivaglobin® Dose  
Mean % Previous IGIV Dose (range): 136% (99 – 188%)
  Mean: 158 mg/kg b.w.
  Range: 34 – 352 mg/kg b.w.
Annual Rate of Serious Bacterial Infections 0.04 infections/subject year
Annual Rate of Any Infections 4.4 infections/subject year
b.w.: body weight

Table 4 provides a summary of missed school or work and hospitalization due to infection, which were secondary endpoints.

Table 4: Summary of Secondary Efficacy Endpoints – Per-protocol Subjects Efficacy Phase of the US and Canada Study

Number of Subjects 51
Total Number of Subject Days 18,949
Total Number of Days Missed School/Work Due to Infection (%) 192 (1.0%)
Annual Rate Missed School/Work Due to Infection (days/subject year) 3.70
Total Number of Days Hospitalized Due to Infection (%) 12 ( < 0.1%)
Annual Rate of Hospitalization (days/subject year) 0.23

In a non-IND clinical study of Vivaglobin® (immune globulin subcutaneous (human)) conducted in Europe and Brazil, 60 adult and pediatric subjects with PID were switched to weekly subcutaneous administration of Vivaglobin® (immune globulin subcutaneous (human)) for six months. Forty-nine (49) subjects had been on IGIV and 11 subjects had been treated long-term with another brand of Immune Globulin Subcutaneous (Human) replacement therapy before entering the study. The forty-seven (47) per-protocol subjects received a weekly mean Vivaglobin® (immune globulin subcutaneous (human)) dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was 101% (range: 81 to 146%) of their previous immune globulin treatment. The annualized rates of serious bacterial infections (0.04 infections/subject year, one-sided upper 99% confidence interval: 0.21) and any infections (4.3 infections/subject year) were similar to those reported in the study conducted in the US and Canada.

REFERENCES

1. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:1208-12.

2. Waniewski I, Gardulf A, Hammarström L. Bioavailability of ã-Globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14(2):90-7.

3. Data on file.

Last reviewed on RxList: 3/3/2009
This monograph has been modified to include the generic and brand name in many instances.

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