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Vivaglobin (Immune Globulin Subcutaneous Human) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Vivaglobin is a sterile solution consisting of pasteurized, polyvalent immune globulin for subcutaneous administration. Vivaglobin is manufactured from large pools of human plasma by cold alcohol fractionation and is not chemically altered or enzymatically degraded. Vivaglobin is a 16% (160 mg/mL) protein solution, with a content of at least 96% IgG. Vivaglobin contains ≤1.7 mg/mL IgA and ≤1.8 mg/mL IgM. The distribution of IgG subclasses is similar to that present in normal human plasma. Vivaglobin also contains 2.25% glycine, 0.3% sodium chloride, and water for injection, USP. The pH of Vivaglobin is 6.4 to 7.2. Vivaglobin contains no preservative.

All plasma units used in the manufacture of Vivaglobin have been tested using serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV as well as Nucleic Acid Testing (NAT) for HIV-1 and HCV and found to be nonreactive (negative). For HBV, an investigational NAT procedure is used and the plasma found to be negative; however, the significance of a negative result has not been established. In addition, the plasma has been tested by NAT for HAV and B19V. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.

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 enveloped and non-enveloped viruses. The virus reduction capacity of two steps (ethanol – fatty alcohol / pH precipitation and pasteurization in aqueous solution at 60°C for 10 hours) was evaluated. Total mean cumulative virus reductions ranged from 9.0 to ≥14.1 log10 as shown in Table 6.

Table 6: Mean Virus Reduction Factors
Virus Studied Ethanol – Fatty Alcohol / pH Precipitation
[log10]
Pasteurization
[log10]
Total Cumulative
[log10]
HIV-1, human immunodeficiency virus type 1, model for HIV-1/2; BVDV, bovine viral diarrhea virus, model for HCV and WNV (West Nile virus); PRV, pseudorabies virus, model for large enveloped DNA viruses (e.g., herpes virus); PEV, porcine enterovirus, model for HAV (in an immune globulin product); CPV, canine parvovirus, model for B19V.
Enveloped Viruses
HIV-1 ≥6.2 ≥6.5 ≥12.7
BVDV ≥5.3 ≥8.7 ≥14.0
WNV ≥4.4 ≥9.3 ≥13.7
PRV ≥6.2 ≥7.9 ≥14.1
Non-enveloped Viruses
PEV ≥6.7 3.7 ≥10.4
CPV 6.7 2.3Reduction of B19V (evaluated using porcine IgG) by pasteurization was ≥5.0 log10. 9.0

CLINICAL PHARMACOLOGY

Mechanism of Action

Vivaglobin supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The mechanism of action in PI has not been fully elucidated.

Pharmacokinetics

The bioavailability of Vivaglobin is approximately 73% compared with IGIV, but can vary significantly among patients (see Clinical Studies [14.1] ). With Vivaglobin, peak serum IgG levels are lower than those achieved with IGIV. Subcutaneous administration results in relatively stable steady-state serum IgG levels when the product is dosed on a weekly basis.12-13

The pharmacokinetics (PK) of Vivaglobin were evaluated in the clinical study conducted in the US and Canada (see Clinical Studies [14.1] ). Subjects previously treated with IGIV were switched to weekly subcutaneous treatment with Vivaglobin. After a 3-month wash-in/wash-out period, doses were adjusted individually aiming to provide an IgG systemic exposure (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 dose adjustment for Vivaglobin was 137% ± 21% SD (range: 103% to 192%) of the previous weekly-equivalent IGIV dose. Following 10 to 12 weeks of treatment with Vivaglobin at this individually adjusted dose, the final steady-state AUC determinations were made in 17 of the 19 per-protocol subjects. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Vivaglobin versus IGIV treatment, was 94.5% (range: 71.4% to 110.1%) with a lower 95% confidence limit of 89.8% for the 17 subjects.

Table 7 summarizes additional pharmacokinetic parameters for this study including dosing and serum IgG peak and trough levels following treatment with IGIV and Vivaglobin.

Table 7: Additional Pharmacokinetic Parameters, US-Canada Study
IGIV Vivaglobin
Number of Subjects 17 17
DoseFor IGIV, weekly-equivalent 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

The 6-month clinical study conducted in Europe and Brazil in 60 subjects with PI also included a PK evaluation. Subjects were treated weekly with Vivaglobin at a mean dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was 101% of their previous weekly IGIV or IGSC dose (see Clinical Studies [14.2] ). After the subjects had reached steady state with weekly administration of Vivaglobin, peak serum IgG levels were observed after a mean of 2.5 days (range: 0 to 7 days) in 41 subjects.

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

CLINICAL STUDIES

US-Canada Study

The open-label, prospective, multicenter clinical study conducted in the US and Canada evaluated the pharmacokinetics, efficacy, safety, and tolerability of Vivaglobin in 65 (51 per-protocol) adult and pediatric subjects with PI. Subjects previously receiving monthly treatment with IGIV were switched to weekly subcutaneous administration of Vivaglobin for 12 months, after a 3-month wash-in/wash-out period.

The study evaluated the annual rate of serious bacterial infections (defined as bacterial pneumonia, meningitis, sepsis, osteomyelitis, and visceral abscesses). The annual rate of any infections was also evaluated.

In this study, the volume of Vivaglobin infused (using administration tubing and an infusion pump) did not exceed 15 mL per injection site at a rate of 20 mL per hour per site. Doses greater than 15 mL were divided and infused into multiple sites using Y-site connection tubing. For recommendations on the number of simultaneous injection sites for pediatric patients weighing less than 45 kg (99 pounds), see Administration .

Table 8 summarizes the dosing and annual rate of infections for the 51 per-protocol subjects in efficacy phase of the US-Canada study.

Table 8: Dose and Annual Rate of Infections with Vivaglobin – Per-protocol Subjects, Efficacy Phase of the US-Canada Study
bw, body weight.
Number of per-protocol subjects
(efficacy phase)
51
Weekly dose of Vivaglobin
  Mean 158 mg/kg bw
  Range 34-352 mg/kg bw
  Mean % previous IGIV dose (range) 136%Actual mean of the median subcutaneous dose administered in the 12-month efficacy phase. (99%-188%)
Annual rate of serious bacterial infections 0.04 infections/subject yearOne-sided upper 99% confidence interval: 0.14%. , Pneumonia was reported in two subjects.
Annual rate of any infections 4.4 infections/subject year

Table 9 provides a summary of missed school or work and hospitalization due to infection, which were also evaluated in the efficacy phase of the study.

Table 9: Additional Efficacy Results – Per-protocol Subjects, US-Canada Study
Number of per-protocol subjects (efficacy phase) 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

Europe-Brazil Study

In a clinical study of Vivaglobin conducted in Europe and Brazil, 60 adult and pediatric subjects with PI were switched to weekly subcutaneous administration of Vivaglobin for 6 months. Forty-nine (49) subjects had been on IGIV, and 11 subjects had been treated long-term with another IGSC before entering the study. The 47 per-protocol subjects received a weekly mean dose of 89 mg/kg body weight of Vivaglobin (range: 51 to 147 mg/kg), which was 101% (range: 81% to 146%) of their previous immune globulin treatment.

The annualized rate of serious bacterial infections was 0.04 infections per subject year (one-sided upper 99% confidence interval: 0.21). The annualized rate of any infections was 4.3 infections per subject year).

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