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Privigen

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Privigen

CLINICAL PHARMACOLOGY

Mechanism of Action

Treatment of Primary Immunodeficiency

Privigen™ (immune globulin intravenous) contains a broad spectrum of antibody specificities. Appropriate doses of Privigen™ (immune globulin intravenous) should restore abnormally low IgG levels to the normal range.

Treatment of Chronic Immune Thrombocytopenic Purpura

The mechanism of action of immunoglobulins in the treatment of chronic ITP is not fully understood. One possible mechanism may be the inhibition of the elimination of autoantibody-reacted platelets from the blood circulation by IgG-induced Fc-receptor blockade of phagocytes.17 Another proposed mechanism is the down-regulation of platelet autoantibody-producing B cells by anti-idiotypic antibodies in IGIV.18

Pharmacokinetics

Treatment of Primary Immunodeficiency

In the clinical study assessing the efficacy and safety of Privigen™ in 80 subjects with PI (see CLINICAL STUDIES), serum concentrations of total IgG and IgG subclasses were measured in 25 subjects (ages 13 to 69) following the 7th infusion for the 3 subjects on the 3-week dosing interval and following the 5th infusion for the 22 subjects on the 4-week dosing interval. 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 pharmacokinetic parameters of Privigen™ (immune globulin intravenous) , measured as serum concentrations of total IgG.

Table 4: Pharmacokinetic Parameters of Privigen™ (immune globulin intravenous) in Subjects with PI

Parameter 3-Week Dosing Interval
(n=3)
4-Week Dosing Interval
(n=22)
Mean
(SD)
Median
(Range)
Mean
(SD)
Median
(Range)
Cmax (peak, mg/dL) 2,550 2,340 2,260 2,340
(400) (2,290-3,010) (530) (1,040-3,460)
Cmin (trough, mg/dL) 1,230 1,200 1,000 1,000
(230) (1,020-1,470) (200) (580-1,360)
t½ (days) 27.6 27.8 45.4 37.3
(5.9) (21.6-33.4) (18.5) (20.6-96.6)
AUC0-t (day mg/dL)* 32,820 29,860 36,390 36,670
(6,260) (28,580-40,010) (5,950) (19,680-44,340)
Clearance (mL/day/kg)* 1.3 1.3 1.3 1.3
(0.1) (1.1-1.4) (0.3) (0.9-2.1)
Cmax, maximum serum concentration; Cmin, trough (minimum level) serum concentration; t½, elimination half-life; AUC0-t, area under the curve from 0 hour to last sampling time.
* Calculated by log-linear trapezoidal rule.

The median half-life of Privigen™ (immune globulin intravenous) was 36.6 days for the 25 subjects in the pharmacokinetic subgroup.

Although no systematic study was conducted to evaluate the effect of gender and age on the pharmacokinetics of Privigen™ (immune globulin intravenous) , based on the small sample size (11 males and 14 females) it appears that clearance of Privigen™ (immune globulin intravenous) is comparable between males (1.27 ± 0.35 mL/day/kg) and females (1.34 ± 0.22 mL/day/kg). In six subjects between 13 and 15 years of age, the clearance of Privigen™ (immune globulin intravenous) (1.35 ± 0.44 mL/day/kg) is comparable to that observed in 19 adult subjects 19 years of age or older (1.29 ± 0.22 mL/day/kg).

The IgG subclass levels observed in the pharmacokinetic study were consistent with a physiologic distribution pattern (mean trough values): IgG1, 564.91 mg/dL; IgG2, 394.15 mg/dL; IgG3, 30.16 mg/dL; IgG4, 10.88 mg/dL.

Treatment of Chronic Immune Thrombocytopenic Purpura

Pharmacokinetic studies with Privigen™ (immune globulin intravenous) were not performed in subjects with chronic ITP.

Clinical Studies

Treatment of Primary Immunodeficiency

A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and pharmacokinetics of Privigen™ (immune globulin intravenous) in adult and pediatric subjects with PI, who were treated for 12 months at a 3-week or 4-week dosing interval. Subjects ranged in age from 3 to 69; 57.5% were female and 42.5% were male; 77.5% were Caucasian, 15% were Hispanic, and 7.5% were African-American. All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study.

The efficacy analysis included 80 subjects, 16 on the 3-week dosing interval and 64 on the 4-week dosing interval. Doses ranged from 200 mg/kg to 888 mg/kg. The median dose for the 3-week interval was 428.3 mg/kg; the median dose for the 4-week interval was 440.6 mg/kg. Subjects received a total of 1038 infusions of Privigen™ (immune globulin intravenous) , 272 in the 3-week dosing interval and 766 in the 4-week dosing interval. The maximum infusion rate allowed during this study was 8 mg/kg/min with 69% (715) of the infusions administered at a rate of 7 mg/kg/min or greater.

The primary endpoint was the annual rate of acute serious bacterial infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess, per subject per year. Secondary endpoints included days out of work/school/day care or days unable to perform normal activities due to illness, days of hospitalization, and use of antibiotics.

During the 12-month study period, the aSBI rate was 0.08 (with an upper 1-sided 99% confidence interval of 0.203), which met the predefined success rate of less than one aSBI per subject per year. Six subjects experienced an aSBI, including three cases of pneumonia and one case each of septic arthritis, osteomyelitis, and visceral abscess. All six subjects completed the study.

The rate of other infections was 3.55 infections per subject per year. The infections that occurred most frequently were sinusitis (31.3%), nasopharyngitis (22.5%), upper respiratory tract infection (18.8%), bronchitis (13.8%), and rhinitis (13.8%). The majority of these infections were mild or moderate; among the 255 infections, 16 (6.3%) occurring in 10 subjects were considered severe.

Table 5 summarizes the efficacy results for all 80 subjects.

Table 5: Summary of Efficacy Results in Subjects With PI

Number of Subjects 80
Results from Case Report Forms
Total Number of Subject Days 26,198
Infections  
Annual rate of confirmed aSBIs* 0.08 aSBIs/subject year†
Annual rate of other infections 3.55 infections/subject year
Antibiotic use
Number of subjects (%) 64 (80%)
Annual rate 87.4 days/subject year
Results from Subject Diaries
Total Number of Diary Days 24,059
Out of work/school/ day care or unable to perform normal activities due to illness  
Number of days (%) 570 (2.37%)
Annual rate 8.65 days/subject year
Hospitalization  
Number of days (%) 166 (0.69%)
Annual rate 2.52 days/subject year
* Defined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess.
† Upper 1-sided 99% confidence interval: 0.203.

Treatment of Chronic Immune Thrombocytopenic Purpura

A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and tolerability of Privigen™ (immune globulin intravenous) in 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less. Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male; all were Caucasian.

Subjects received a 2 g/kg dose of Privigen™ (immune globulin intravenous) administered daily as two 1 g/kg intravenous infusions for 2 consecutive days and were observed for 29 days. Fifty-three (93%) subjects received Privigen™ (immune globulin intravenous) at the maximum infusion rate allowed (4 mg/kg/min [0.04 mL/kg/min]).

The primary endpoint was the response rate defined as the percentage of subjects with an increase in platelet counts to at least 50 x 109/L within 7 days after the first infusion (responders). Secondary endpoints included the increase in platelet counts and the time to reach a platelet count of at least 50 x 109/L at any point within the study period, the duration of that response, and the regression (decrease in the severity) of hemorrhage in subjects who had bleeding at baseline. Platelet counts were measured on Days 1, 2, 4, 6, 8, 15, 22, and 29. Additional measurements on Days 57 and 85 occurred in subjects with a platelet count of at least 50 x 109/L at the previous visit.

Of the 57 subjects in the efficacy analysis, 46 (80.7%) responded to Privigen™ (immune globulin intravenous) with a rise in platelet counts to at least 50 x 109/L within 7 days after the first infusion. The lower bound of the 95% confidence interval for the response rate (69.2%) is above the predefined response rate of 50%.

The highest median increase in platelet counts was seen 7 days after the first infusion (123 x 109/L). The median maximum platelet count achieved was 154 x 109/L. The median time to reach a platelet response of more than 50 x 109/L was 2.5 days after the first infusion. Twenty-five (43%) of the 57 subjects reached this response by Day 2 prior to the second infusion and 43 (75%) subjects reached this response by Day 6.

The duration of platelet response was analyzed for the 48 subjects who achieved a response any time after the first infusion. The median duration of platelet response in these subjects was 15.4 days (range: 1 to > 82 days). Thirty-six (75%) of the 48 subjects maintained the response for at least 8.8 days and 12 (25%) of them for at least 21.9 days. Five (9%) subjects maintained a response up to Day 29 and two (4%) up to Day 85.

A decrease in the severity of hemorrhage from baseline was observed in the following bleeding locations: skin (31 of 36 subjects), oral cavity (11 of 11 subjects), and genitourinary tract (7 of 9 subjects). This decrease was not sustained in all subjects up to the end of the 29-day study period.

REFERENCES

17. Bussel JB. Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol 2000; 37:261-266.
18. Lazarus AH, Freedman J, Semple JW. Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci 1998;19:289-294.

Last reviewed on RxList: 8/27/2007
This monograph has been modified to include the generic and brand name in many instances.

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