terval.
The dose of ASCENIV used in thesesubjects ranged from 291 mg/kg to 760 mg/kg. After the infusion, blood samples were taken until Day 28 after infusion forthe 4-week dosing interval and until Day 21 after infusion for the 3-week dosing interval. Table 4 summarizes the Total IgGPharmacokinetic Parameters of ASCENIV, based on serum concentration of total IgG. The mean ± SD half-life of ASCENIVwas 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 intervalfor the 30 subjects in the pharmacokinetic subgroup. Although no systematic study was conducted to eva luate the effect ofsex on the pharmacokinetics of ASCENIV, based on the small sample size (11 males and 19 females) the pharmacokineticsof ASCENIV was comparable between males and females. In adolescents the pharmacokinetics of ASCENIV wascomparable with adults. There were insufficient PK data in children younger than 12 years.
Table 4: Total IgG Pharmacokinetic Parameter Estimates (PK Population) in Subjects
3-week cycle
(n = 10)
4-week cycle
(n = 20)
Statistic Mean (SD) CV% Mean (SD) CV%
Cmax (mg/dL) 2,427 (452) 18.6 2,227 (584) 26.2
Cmin (mg/dL) 1,152 (308) 26.7 954 (245) 25.7
Tmax (h) a 2.93 (1.8, 4.5) NA 2.78 (1.43, 99.1) NA
AUCtau (d*mg/dL) 32,128 (7,020) 21.9 35,905 (9,351) 26.0
t½ (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
Vss (mL/kg) 76.79 (13.5) 17.5 89.57 (26.2) 29.2
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; t½ = terminal half-life;
Vss = Volume of distribution steady-state; a median (range)
Table 5: Total IgG Pharmacokinetic Parameter Estimates (PK Population) in Subjects—Baseline Corrected
3-week cycle 4-week cycle
Statistic Mean (SD) CV% N Mean (SD) CV% N
Cmax (mg/dL) 1223 (297) 24.2
10 1231 (453) 37 20
Cmin (mg/dL) 19 (31) 166
10 46 (42) 178 20
Tmax (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
t½ (d) 6 (2) 41
5 10 (8) 80 9
CL (mL/d/kg) 9 (4) 42
10 8 (5) 61 20
Vz (mL/kg) 82 (62) 75
5 82 (35) 43 9
AUC(0-t) = steady-state area under the plasma concentration versus time curve with 0-t = dosing interval; CL = totalbody clearance;
Cmax = maximum concentration; Cmin = minimum concentration; CV = coefficient of variation; N = number of subjects;
SD = standard deviation; Tmax = time of maximum concentration; t½ = terminal half-life;
Vz = Apparent Volume of distribution during terminal phase;
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies were conducted to eva luate the carcinogenic or mutagenic effects of ASCENIV or its effects on fertility.
13.2 Animal Toxicology and/or Pharmacology
No animal studies were conducted to eva luate possible toxicity of ASCENIV.
ASCENIV contains Polysorbate 80; Intravenous administrations of Polysorbate 80 in multiple species have been linked with adecrease in blood pressure. In rats, single doses of Polysorbate 80 that were up to 25 times higher than the amount from 800mg/kg ASCENIV resulted in an increase of liver enzymes and total bilirubin.
14 CLINICAL STUDIES
A prospective, op |
