treatment" and "35 nm virus filtration." In compliance with current guidelines, the steps have been separately validated in a seriesof in vitro experiments for their capacity to inactivate or remove both enveloped and nonenveloped viruses.
Precipitation and removal of fraction III removes both enveloped and non-enveloped viruses, solvent/detergent treatmentrepresents a virus inactivation step for enveloped viruses, and 35 nm virus filtration removes both enveloped and non-envelopedviruses by size exclusion. In addition to the steps above, low pH during several steps of the production process contributes to virusinactivation. The results of virus validation studies for ASCENIV are shown in Table 3, expressed as log10 reduction factors.
Table 3: Virus Validation Data for ASCENIV
Virus Reduction (log10)
Virus Type
Family
Enveloped Viruses Non-enveloped Viruses
Retro Flavi Herpes Parvo Picorna Polyoma
Step / Test
Virus HIV BVDV SinV WNV PRV PPV BPV MEV SV40
Precipitation
and Removal of
Fraction III and
Depth Filtration
- 1.87* - - - 4.00 - 5.29 2.00*
TnBP/Triton X-
100 Treatment > 4.43 > 5.04 > 7.11 > 4.96 > 4.01 - - - -
35 nm Virus
Filtration > 5.19 > 4.88 - - > 4.64 < 1.0 6.18 < 1.0 > 5.02
Total Clearance > 9.62 > 11.79 > 7.11 > 4.96 > 8.65 4.00 6.18 5.29 > 7.02
* without depth filtration
-- not done
values below 1 log10 are considered insignificant and are not used for total clearance;HIV, human immunodeficiency virus; BVDV, Bovine viral diarrhea virus, model virus for HCV; SinV, Sindbis virus, model virusfor HCV; WNV, West Nile virus; PRV, Pseudorabies virus, model virus for herpes viruses and Hepatitis B virus; MEV, Murineencephalomyelitis virus, model virus for hepatitis A virus; BPV, Bovine parvovirus, model virus for human B19 virus; PPV,Porcine parvovirus, model virus for human B19 virus; SV40, Simian virus 40, model virus for highly resistant non-envelopedviruses.
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 avoidrecurrent serious opportunistic infections. IgG antibodies are opsonins that increase phagocytosis and elimination ofpathogens 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 than1,000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of IGIV can restore anabnormally 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 wereeva luated 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 in |
