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Mechanism Of Action
BIVIGAM is a replacement therapy in patients with primary humoral immunodeficiency (PI) (e.g. agammaglobulinaemia, hypogammaglobulinaemia, CVID, SCID).
The broad spectrum of neutralizing IgG antibodies against bacterial and viral pathogens and their toxins helps to avoid recurrent serious opportunistic infections. IgG antibodies are opsonins that increase phagocytosis and elimination of pathogens from the circulation. The mechanism of action has not been fully elucidated in PI.
In the clinical study assessing the efficacy and safety of BIVIGAM in 63 subjects with PI (see Clinical Studies), serum concentrations of total IgG and IgG subclasses were measured in 21 subjects (ages 18 to 75) following the 4th infusion for the 5 subjects on the 3-week dosing interval and following the 5th infusion for the 16 subjects on the 4-week dosing interval. The dose of BIVIGAM used in these subjects ranged from 300 mg/kg to 800 mg/kg. After the infusion, blood samples were taken until Day 21 and Day 28 for the 3-week and 4-week dosing intervals, respectively. Table 4 summarizes the Total IgG Pharmacokinetic Parameters of BIVIGAM, based on serum concentrations of total IgG. Trough concentrations were maintained throughout the study for both treatment cycles and mean trough concentrations were well above the target trough concentration of 500 mg/dL for both treatment cycles in pediatric (? 6 years old) as well as adult subjects at all time points.
Table 4: Total IgG Pharmacokinetic Parameter Estimates
(PK Population) in Adults
(n = 5)
(n = 21)
|Mean (SD)||CV%||Mean (SD)||CV%||Mean (SD)||CV%|
|Cmax(mg/dL)||2184 (293)||13.4||2122 (425)||20.0||2137 (392)||IS.3|
|Cmin (mg/dL)||996 (176)||17.6||1106 (396)||35.8||1080 (355)||32.9|
|Tmax (h)a||4.05 (2.67- 26.1)||NA||3,47 (2.58- 78.6)||NA||3.50 (2.58- 78.6)||NA|
|AUCtau (day*mg/dL)||27841 (4925)||17.7||35509 (6472)||18.2||33592 (6S9S)||20.5|
|t½(d)||19.6 (4.1)||21.1||33,5 (10.7)||32.0||30,0 (11.2)||37.5|
|CL (dL/kg/d)||Q.Q197 (0.002234)||11.3||0.0141 (0.00463)||32.8||0.0155 (0.00480)||31.0|
|Vss (dL/kg)||0.5S4 (0.132)||22,6||0,640 (0.141)||22.1||0.626 (0,138)||22.0|
|MRT (day)||29.5 (5.1)||17.54||48.3 (14.6)||30.2||43,6 (15.2)||35.0|
|AUCtau = steady-state area under the plasma concentration versus time curve with tau = dosing interval; CL = total body clearance; Cmax = maximum concentration; Cmin = minimum concentration; CV = coefficient of variation; n = number of subjects; NA = not applicable; SD = standard deviation; Tmax = time of maximum concentration; t = terminal half-life; Vss = Volume of distribution steady-state; MRT = mean residence time; a Median and Range. The median terminal half-life of BIVIGAM was 30 days for the 21 subjects. Mean trough IgG subclass levels were consistent with physiological values.|
Animal Toxicology And/Or Pharmacology
No animal studies were conducted to evaluate possible toxicity of BIVIGAM in animals.
BIVIGAM contains Polysorbate 80 at a concentration of up to 2.5 mg/mL. Intravenous administrations of Polysorbate 80 in multiple species have been linked with a decrease in blood pressure. In rats, single doses of Polysorbate 80 that were up to 25 times higher than the amount from 800 mg/kg BIVIGAM resulted in an increase of liver enzymes and total bilirubin.
Treatment Of Primary Humoral Immunodeficiency
?A prospective, open-label, single-arm, multicenter trial assessed the efficacy, safety, and pharmacokinetics of BIVIGAM in adult and pediatric subjects with PI. Study subjects were receiving regular IGIV replacement therapy, with a stable dose between 300 and 800 mg/kg for at least 3 months prior to participation. Subjects received a BIVIGAM infusion administered every 3 or 4 weeks (both the dose and schedule depending on their prior therapy) for approximately 1 year.
A total of 63 subjects were enrolled in the trial, 31 men and 32 women with a mean age of 41 years. Fourty-four subjects were adults (70%) between 18 and 64 years of age. There were 9 pediatric subjects (see Pediatric Use), and 9 elderly subjects (14%, ?65 years of age). The oldest subject was 75 years of age. There were 17 subjects with a 3-week cycle and 46 subjects with a 4-week cycle. There were 51 subjects (81%) with common variable immunodeficiency as their primary diagnosis, followed by X-linked agammaglobulinemia and Other (9.5% each). The intent to treat (ITT) population included 58 subjects and was used for efficacy analysis.
The primary endpoint of the study was to assess the efficacy of BIVIGAM in preventing serious bacterial infections (SBIs) defined as rate of less than 1.0 cases of bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis per person-year. Secondary efficacy parameters included time to first SBI and time to first infection of any kind/seriousness, days on antibiotics (excluding prophylaxis), days offschool/work due to infections, all confirmed infections of any kind or seriousness, and hospitalizations due to infection.
During the 12-month study period, two serious acute bacterial infections occurred in two subjects with an onset date between the first infusion of BIVIGAM and the first follow-up visit, inclusive. Thus, the mean event rate of serious, acute, bacterial infections per year was 0.037 (with an upper 1-sided 99% confidence interval of 0.101, which met the study s primary efficacy endpoint).
The two SBIs were cases of bacterial pneumonia. Thirty-three percent of subjects had days off work or school due to an infection. Of the 197 infections reported, 2 resulted in hospitalization. Results for the pediatric subjects were similar to those for the adult subjects. (see Table 5).
Table 5: Summary of Efficacy Results in Subjects with
|Number of Subjects (ITT Population)||58|
|Total Number of person-yearsa||53.5|
|Number of confirmed serious acute bacterial infectionsb|
|Rate of SBIs (SB I s/total person-years)||0.037|
|Infections per subject per year||3.7|
|Number of sub jects (%)||50 (S6%)|
|Days per subject per year||39.1|
|Davs off schooL'work clue to infections|
|Number of persons with days off of school or work due to infections (%)||21 (36%)|
|Total days (%)||122 (0.6%)|
|Days per subject per year||2.3|
|Number of subjects (%)||2 (3.4%)|
|Number of Days||11 (0.06%)|
|Days per subject per year||0.21|
|SBI = serious bacterial infections.
aPerson-years: Person-time in years with 2 decimals = (the Final Clinical Visit Date - the Day 0 date+1)/ 365.25, where the final clinical visit date is defined as the specimen collection date of the final clinical visit for urinalysis, or the specimen collection date for the clinical laboratory tests at the final clinical visit and Day 0 date is the start date of the first BIVIGAM infusion.
b Defined as bacterial pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess.
c The calculation of antibiotic use excludes 8 subjects who were on antibiotics throughout the study either prophylactically or for ongoing or recurrent conditions.
Last reviewed on RxList: 12/5/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Bivigam Information
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