April 29, 2016
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Privigen

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Privigen




CLINICAL PHARMACOLOGY

Mechanism Of Action

Treatment Of Primary Humoral Immunodeficiency

Privigen is a replacement therapy for primary humoral immunodeficiency, and supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacterial, viral, parasitic and mycoplasma agents and their toxins. The mechanism of action in PI has not been fully elucidated.

Treatment Of Chronic Immune Thrombocytopenic Purpura

The mechanism of action of high doses of immunoglobulins in the treatment of chronic ITP has not been fully elucidated.

Pharmacokinetics

Treatment Of Primary Humoral Immunodeficiency

In the clinical study (pivotal 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. The dose of Privigen used in these subjects ranged from 200.0 mg/kg to 714.3 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 6 summarizes the pharmacokinetic parameters of Privigen, based on serum concentrations of total IgG.

Table 6: PI Pivotal Study - Pharmacokinetic Parameters of Privigen in Subjects

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
(400)
2,340
(2,290-3,010)
2,260
(530)
2,340
(1,040-3,460)
Cmin
(trough, mg/dL)
1,230
(230)
1,200
(1,020-1,470)
1,000
(200)
1,000
(580-1,360)

(days)
27.6
(5.9)
27.8
(21.6-33.4)
45.4
(18.5)
37.3
(20.6-96.6)
AUC0-t
(day x mg/dL)*
32,820
(6,260)
29,860
(28,580- 40,010)
36,390
(5,950)
36,670
(19,680- 44,340)
* /dL g/ m x TO
(d S C0 U A
79,315
(20,170)
78,748
(59,435- 99,762)
104,627
(33,581)
98,521
(64,803- 178,600)
Clearance
(mL/day/kg)*
1.3
(0.1)
1.3
(1.1-1.4)
1.3
(0.3)
1.3
(0.9-2.1)
Mean residence time
(days)*
38.6
(8.1)
39.5
(30.1-46.2)
65.2
(24.7)
59.0
(33.2-129.6)
Volume of distribution at steady state
(mL/kg)*
50
(13)
44
(40-65)
84
(35)
87
(40-207)
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; AUC0-∞, area under the curve from 0 hour to infinite time.
* Calculated by log-linear trapezoidal rule.

The median half-life of Privigen 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, based on the small sample size (11 males and 14 females) it appears that clearance of Privigen is comparable in 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 (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 were not performed in subjects with chronic ITP.

Clinical Studies

Treatment Of Primary Humoral Immunodeficiency

A prospective, open-label, single-arm, multicenter study (pivotal study) assessed the efficacy, safety, and pharmacokinetics of Privigen 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; 46 (57.5%) were male and 34 (42.5%) were female; 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 (20%) on the 3-week dosing interval and 64 (80%) on the 4-week dosing interval. Doses ranged from 200 mg/kg to 888 mg/kg per infusion. The median dose for the 3-week interval was 428.3 mg/kg per infusion; the median dose for the 4-week interval was 440.6 mg/kg per infusion. Subjects received a total of 1038 infusions of Privigen, 272 for the 3-week dosing regimen and 766 for the 4-week dosing regimen. The maximum infusion rate allowed during this study was 8 mg/ kg/min with 715 (69%) of the infusions administered at a rate of 7 mg/kg/min or greater. The primary analysis for efficacy was based on 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 analyses were based on the annual rate of other infections, antibiotic use, days out of work/school/ day care or unable to perform normal activities due to illness, and days of hospitalization. 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%). Among the 255 infections, 16 (6.3%) occurring in 10 subjects were considered severe.

Table 7 summarizes the efficacy results for all 80 subjects.

Table 7: PI Pivotal Study – Summary of Efficacy Results in Subjects

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 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; 23 (40.4%) were male and 34 (59.6%) were female; all were Caucasian.

Subjects received a 2 g/kg dosage of Privigen administered as 1 g/kg (10 mL/kg) intravenous infusion daily for 2 consecutive days, and were observed for 29 days. Fifty-three (93%) subjects received Privigen at the maximum infusion rate allowed (4 mg/kg/min [0.04 mL/kg/min]).

The primary analysis was based on 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 analyses were based on 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 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.

Last reviewed on RxList: 3/18/2016
This monograph has been modified to include the generic and brand name in many instances.

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