ASCENIV (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ASCENIV is a replacement therapy for patients with primary humoral immunodeficiency (PI) (e.g. agammaglobulinemia, hypogammaglobulinemia, 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.

12.2 Pharmacodynamics

ASCENIV contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents, reflecting the IgG activity found in the donor population. ASCENIV which is prepared from pooled plasma from not less than 1,000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of IGIV can restore an abnormally low IgG level to the normal range. Standard pharmacodynamics studies were not performed.

12.3 Pharmacokinetics

In a prospective, open-label, single-arm, multicenter clinical study, efficacy, safety and pharmacokinetics of ASCENIV were evaluated in 59 subjects with PI ( See Clinical Studies [14]). Serum concentrations of total IgG were measured in 30 subjects (four subjects, ages 7 to 16 years and 26 subjects from 17 to 74 years) following the seventh infusion for subjects on a 4-week dosing interval and the ninth infusion for subjects on a 3-week dosing interval. The dose of ASCENIV used in these subjects ranged from 291 mg/kg to 760 mg/kg. After the infusion, blood samples were taken until Day 28 after infusion for the 4-week dosing interval and until Day 21 after infusion for the 3-week dosing interval. Table 4 summarizes the Total IgG Pharmacokinetic Parameters of ASCENIV, based on serum concentration of total IgG. The mean ± SD half-life of ASCENIV was 28.5 ± 4.4 days for subjects on a 3-week dosing interval and 39.7 ± 11.6 days for subjects on a 4-week dosing interval for the 30 subjects in the pharmacokinetic subgroup. Although no systematic study was conducted to evaluate the effect of sex on the pharmacokinetics of ASCENIV, based on the small sample size (11 males and 19 females) the pharmacokinetics of ASCENIV was comparable between males and females. In adolescents, the pharmacokinetics of ASCENIV was comparable with adults. There were insufficient PK data in children younger than 12 years.

Table 4: Total IgG Pharmacokinetic Parameter Estimates (PK Population) in Subjects
AUC tau = steady-state area under the plasma concentration versus time curve with tau = dosing interval; CL = total body clearance; C max = maximum concentration; C min = minimum concentration; CV = coefficient of variation; n = number of subjects; NA = not applicable; SD = standard deviation; T max = time of maximum concentration; t ½ = terminal half-life; V ss = Volume of distribution steady-state; a median (range)
3-week cycle (n = 10) 4-week cycle (n = 20)
Statistic Mean (SD) CV% Mean (SD) CV%
C max (mg/dL) 2,427 (452) 18.6 2,227 (584) 26.2
C min (mg/dL) 1,152 (308) 26.7 954 (245) 25.7
T max (h) a 2.93 (1.80, 4.52) NA 2.78 (1.43, 99.1) NA
AUC tau (d * mg/dL) 32,128 (7,020) 21.9 35,905 (9,351) 26.0
t ½ (d) 28.47 (4.4) 15.4 39.70 (11.6) 29.1
CL (mL/d/kg) 1.68 (0.4) 25.4 1.47 (0.5) 33.6
V ss (mL/kg) 76.79 (13.5) 17.5 89.57 (26.2) 29.2
Table 5: Total IgG Pharmacokinetic Parameter Estimates (PK Population) in Subjects—Baseline Corrected
AUC (0-t) = steady-state area under the plasma concentration versus time curve with 0-t = dosing interval; CL = total body clearance; C max = maximum concentration; C min = minimum concentration; CV = coefficient of variation; N = number of subjects; SD = standard deviation; T max = time of maximum concentration; t ½ = terminal half-life; V z = Apparent Volume of distribution during terminal phase;
3-week cycle 4-week cycle
Statistic Mean (SD) CV% N Mean (SD) CV% N
C max (mg/dL) 1223 (297) 24.2 10 1231 (453) 37 20
C max (mg/dL) 19 (31) 166 10 46 (42) 178 20
T max (h) 3.04 (0.8) 27 10 8 (22) 282 20
AUC (0-t) (d*mg/dL) 6604 (2913) 44 10 7936 (3482) 44 20
t ½ (d) 6 (2) 41 5 10 (8) 80 9
CL (mL/d/kg) 9 (4) 42 10 8 (5) 61 20
V z (mL/kg) 82 (62) 75 5 82 (35) 43 9

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