Babybig (Botulism Immune Globulin) - Description and Clinical Pharmacology

DESCRIPTION

BabyBIG, Botulism Immune Globulin Intravenous (Human) (BIG-IV), is a solvent-detergent-treated, sterile, lyophilized powder of immunoglobulin G (IgG), stabilized with 5% sucrose and 1% albumin (human). It contains no preservative. The purified immunoglobulin is derived from pooled adult plasma from persons who were immunized with pentavalent botulinum toxoid and selected for their high titers of neutralizing antibody against botulinum neurotoxins type A and B. All donors were tested and their sera found to be negative for antibodies against the human immunodeficiency virus and the hepatitis B and hepatitis C viruses.

The pooled plasma was fractionated by cold ethanol precipitation of the proteins according to the Cohn/Oncley method, modified to yield a product suitable for intravenous administration.^[24,25] Several steps in the manufacturing process have been validated for their ability to inactivate or remove viruses that may not have been detected in the Source Plasma.^[1,26-29] These include Cohn/Oncley fractionation (Fraction I through Supernatant III Filtrate); nanofiltration through one 75-nm and two 35-nm filters; and solvent/detergent viral inactivation. These viral reduction steps have been validated in a series of in vitro experiments for their capacity to inactivate and/or remove Human Immunodeficiency Virus type 1 (HIV-1) and the following model viruses: bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; mouse encephalomyelitis virus (MEMV) as a model for hepatitis A virus; and pseudorabies virus (PRV), feline calicivirus (FCV), and Sindbis virus to cover a wide range of physicochemical properties in the model viruses studied. Total mean log₁₀ reductions range from 4.63 to greater than 16 log₁₀ as shown in the following table.

Process Step	Mean Reduction Factor (log10)
	Enveloped Viruses (size in nm)				Non-Enveloped Viruses (size in nm)
	Sindbis (60-70)	HIV-1 (80-100)	PRV (120-200)	BVDV (40-60)	MEMV (22-30)	FCV (35-39)
Cohn/Oncley fractionation	6.6	> 9.44	> 10.37	6.25	4.06	Not done
Nanofiltration	≥ 6.84	Not done	Not done	≥ 5.4	Not done	≥ 6.92
Solvent/detergent treatment	Not done	> 4.51	> 5.53	> 4.85	0.57Included hydrophobic chromatography after solvent/detergent treatment.	Not done
Cumulative Reduction Factor (log10)	≥ 13.44	> 13.95	> 15.9	≥ 16.5	4.63	≥ 6.92

Additional testing performed with bovine parvovirus (as a model for parvovirus B19) showed a mean cumulative reduction factor of greater than 7.34 log₁₀ for Cohn/Oncley fractionation and solvent/detergent treatment followed by hydrophobic chromatography. A mean cumulative reduction factor of 2.55 log₁₀ was observed for removal of porcine parvovirus by nanofiltration.

When reconstituted with Sterile Water for Injection USP, each cubic centimeter (milliliter) contains approximately 50 ± 10 mg immunoglobulin, primarily IgG, and trace amounts of IgA and IgM; 50 mg sucrose; 10 mg albumin (human); and approximately 20 x 10^-3 mEq sodium. The reconstituted solution should appear colorless and translucent [ see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS (5) ].

CLINICAL PHARMACOLOGY

BabyBIG contains IgG antibodies from the immunized donors who contributed to the plasma pool from which the product was derived. The titer of antibodies in the reconstituted product against type A botulinum toxin is at least 15 IU/mL and against type B toxin is at least 2.7 IU/mL. For toxin types A and B, by definition, 1 IU of botulinum antitoxin neutralizes 10,000 intraperitoneal mouse LD₅₀ of botulinum toxin. The titers of antibody against botulinum neurotoxins C, D, and E have not been determined. In the case of infants who may be exposed to botulinum neurotoxin type A or B, this product is expected to provide the relevant antibodies at levels sufficient to neutralize the expected levels of circulating neurotoxin.^{[14, 30]}

Mechanism of Action

BabyBIG contains antibodies specific for botulinum neurotoxin types A and B that bind to and neutralize circulating toxin types A and B in the patient.

Pharmacodynamics

Formal studies on pharmacodynamics have not been conducted with BabyBIG.

Pharmacokinetics

Traditional pharmacokinetic studies of BabyBIG have not been performed. However, the following table summarizes the mean serum titer of the anti-A component of BabyBIG following administration.

Time	BabyBIG Lot 1 Anti-A Titer (mean ± S.D.)	BabyBIG Lot 2 Anti-A Titer (mean ± S.D.)
	mIU/mL
NOTE: 1 IU of anti-type A or anti-type B antibody neutralizes, by definition, 104 mouse LD50 of botulinum toxin.
Day 1	Not done	537.1 ± 213.4
Week 2	106.7 ± 44.6	192.2 ± 71.2
Week 4	90.0 ± 39.2	155.5 ± 56.7
Week 8	54.9 ± 22.8	96.0 ± 33.2
Week 12	26.0 ± 20.5	61.4 ± 32.3
Week 16	15.6 ± 10.4	33.0 ± 22.3
Week 20	7.6 ± 6.6	19.3 ± 14.1

The half-life of injected BabyBIG has been shown to be approximately 28 days in infants,^[14] which is in agreement with existing data for other immunoglobulin preparations.^[2,14]

CLINICAL STUDIES

Two clinical studies in infant botulism were performed: (1) an adequate and well-controlled study to evaluate the safety and efficacy of BabyBIG (N=129), and (2) an open label study to collect additional safety data and confirm efficacy (N=293). In the adequate and well-controlled clinical study, BabyBIG, given within the first 3 days of hospital admission to 59 patients with laboratory-confirmed infant botulism, has been shown to reduce the following:

	Average Length in Weeks		p-value
	Placebo Both Gammagard 5% and Gammagard S/D 5% were used as placebo in this study. N=63	BabyBIG N=59
Hospital stay	5.7	2.6	p<0.0001
Intensive Care Unit stay	3.6	1.3	p<0.01
Mechanical ventilation	2.4	0.7	p<0.05
Tube-feeding	10.0	3.6	p<0.01

Length of hospital stay was also analyzed by patient age in both the adequate and well-controlled study and in an open label study.

Age (days)	Mean Length of Hospital Stay in Weeks
	Placebo Both Gammagard 5% and Gammagard S/D 5% were used as placebo in this study. N=63	BabyBIG (RCT) N=59	BabyBIG (OLS) N=206
RCT = randomized clinical trial OLS = open label study
0-60	3.8 (N=10)	2.8 (N=10)	2.0 (N=46)
61-120	5.6 (N=29)	1.9 (N=17)	2.0 (N=68)
>120	6.6 (N=24)	3.0 (N=32)	1.8 (N=92)

The observed reduction in length of hospital stay was statistically significant (p<0.01) with the exception of the 0 to 60-day age stratum, where small patient numbers limited the statistical power.

Length of hospital stay was analyzed in the adequate and well-controlled study by race (white versus non-white):

	Mean Length of Hospital Stay in Weeks
Race	Placebo Both Gammagard 5% and Gammagard S/D 5 % were used as placebo in this study.	BabyBIG (RCT)
White	6.3 (N=40)	2.8 (N=35)
Non-white	4.6 (N=23)	2.4 (N=24)

Length of hospital stay was significantly reduced in both white and non-white patients (p=0.002).

BabyBIG has not been tested for safety and efficacy in adults.