DESCRIPTION
ARALAST NP is a sterile, stable, lyophilized preparation of
purified human alpha1–proteinase inhibitor
(α1–PI), also known as
alpha1–antitrypsin.1 ARALAST NP is a similar
product to ARALAST, containing the same active components of plasma
α1-PI with identical formulations.
ARALAST NP is prepared from large pools of human plasma by using
the cold ethanol fractionation process, followed by purification steps
including polyethylene glycol and zinc chloride precipitations and ion
exchange chromatography. All U.S. licensed α1-PI plasma
derived products contain chemical modifications which arise during
manufacturing and occur in varying levels from product to
product.11 ARALAST NP contains approximately 2%
α1-PI with truncated C-terminal lysine (removal of
Lys394), whereas ARALAST contains approximately 67% α1-PI
with the C-terminal lysine truncation.12 No known data
suggest influence of these structural modifications on the functional
activity and immunogenicity of
α1-PI.13
To reduce the risk of viral transmission, the manufacturing
process includes treatment with a solvent detergent (S/D) mixture
[tri–n–butyl phosphate and polysorbate 80] to inactivate enveloped viral
agents such as human immunodeficiency virus (HIV), hepatitis B (HBV),
and hepatitis C (HCV). In addition, a nanofiltration step is
incorporated into the manufacturing process to reduce the risk of
transmission of enveloped and non–enveloped viral agents. Based on
in vitro studies, the process
used to produce ARALAST NP has been shown to inactivate and/or partition
various viruses as shown in Table 1
below.2
Table 1: Virus Log
Reduction in ARALAST NP Manufacturing Process
Processing Step
|
Virus Log Reduction
Factors
|
HIV-1
|
BVDV
|
PRV
|
HAV
|
MMV
|
Cold ethanol fractionation |
4.6 |
1.4 |
2.1 |
1.4 |
< 1.0
|
Solvent Detergent-treatment |
>
5.8 |
>
6.0 |
>
5.5 |
N/A
|
N/A
|
15 N nanofiltration |
>
5.3 |
>
6.0 |
>
5.6 |
>
5.1 |
4.9
|
Overall reduction factor
|
>
15.7
|
> 13.4
|
> 13.2
|
> 6.5
|
4.9
|
HIV-1: Human immunodeficiency virus-1, BVDV
(Bovine Viral Diarrhea Virus, model for Hepatitis C Virus
and other lipid enveloped RNA viruses), PRV (Pseudorabies
Virus, model for lipid-enveloped DNA viruses, to wich also
hepatitis B belongs): HAV: Hepatitus A Virus, MMV (Mice
Minute Virus, model for small non-lipid enveloped DNA
viruses) |
The unreconstituted, lyophilized cake should be white or
off-white to slightly yellow-green or yellow in color. When
reconstituted as directed, the concentration of functionally active
α1–PI is ≥16 mg/mL and the specific activity is ≥0.55 mg
active α1–PI/mg total protein. The composition of the
reconstituted product is as follows:
Component
|
Quality/mL
|
Elastase Inhibitory
Activity |
≥400 mg Active
α1–PI/0.5 g vial* |
| ≥800 mg Active
α1–PI/1.0 g vial** |
Albumin |
≤5 mg/mL |
Polyethylene Glycol |
≤112 µg/mL |
Polysorbate 80 |
≤50 µg/mL |
Sodium |
≤230 mEq/L |
Tri-n-buyl Phosphate |
≤1.0 µg/mL |
Zinc |
≤3 ppm |
* Reconstitution volume: 25mL/0.5 g vial
** Reconstitution volume: 50mL/1.0 g vial |
Each vial of ARALAST NP is labeled with the amount of
functionally active α1–PI expressed in mg/vial. The
formulation contains no preservative. The pH of the solution ranges from
7.2 to 7.8. Product must only be administered intravenously.
|
CLINICAL PHARMACOLOGY
ARALAST NP functions in the lungs to inhibit serine proteases
such as neutrophil elastase (NE), which is capable of degrading protein
components of the alveolar walls and which is chronically present in the
lung. In the normal lung, α1–PI is thought to provide more
than 90% of the anti–NE protection in the lower respiratory
tract.3,4
α1–PI deficiency is an autosomal, co-dominant,
hereditary disorder characterized by low serum and lung levels of
α1–PI.1,3,5,6 Severe forms of the deficiency
are frequently associated with slowly progressive, moderate-to-severe
panacinar emphysema that most often manifests in the third to fourth
decades of life, resulting in a significantly lower life
expectancy.1,3,4,6,7 However, an unknown percentage of
individuals with severe α1–PI deficiency are not diagnosed
with or may never develop clinically evident emphysema during their
lifetimes. Individuals with α1–PI deficiency have little
protection against NE released by a chronic, low–level of neutrophils in
their lower respiratory tract, resulting in a protease:protease
inhibitor imbalance in the lung.3,8 The emphysema associated
with severe α1–PI deficiency is typically worse in the lower
lung zones.5 It is believed to develop because there are
insufficient amounts of α1–PI in the lower respiratory tract
to inhibit NE. This imbalance allows relatively unopposed destruction of
the connective tissue framework of the lung
parenchyma.8
There are a large number of phenotypic variants of this
disorder.1,3,4 Individuals with the PiZZ variant
typically have serum α1–PI levels less than 35% of the
average normal level.1,5 Individuals with the Pi(null)(null)
variant have undetectable α1–PI protein in their
serum.1,3 Individuals with these low serum
α1-PI levels, i.e., less than 11 µM, have an increased risk
of developing emphysema over their lifetimes. In addition, PiSZ
individuals, whose serum α1-PI levels range from
approximately 9 to 23 μΜ14, are considered to have moderately
increased risk for developing emphysema, regardless of whether their
serum α1-PI levels are above or below 11 μΜ. Two
Registry studies have shown 54% and 72% of α1-PI deficient
individuals had emphysema and pulmonary symptoms such as cough, phlegm,
wheeze, breathlessness, and chest colds, respectively.9,10
The risk of accelerated development and progression of emphysema in
individuals with severe α1–PI deficiency is higher in smokers
than in ex-smokers or non-smokers.3
Not all individuals with severe genetic variants of
α1-PI deficiency have emphysema. Augmentation therapy with Alpha1-Proteinase Inhibitor
(Human) is indicated only in patients with congenital
α1-PI deficiency who have clinically evident
emphysema.
Augmenting the levels of functional α1-proteinase
inhibitor by intravenous infusion is an approach to therapy for patients
with α1-PI deficiency. However, the efficacy of augmentation
therapy in affecting the progression of emphysema has not been
demonstrated in randomized, controlled clinical trials. The intended
theoretical goal is to provide protection to the lower respiratory tract
by correcting the imbalance between neutrophil elastase and protease
inhibitors. Whether augmentation therapy with ARALAST NP actually
protects the lower respiratory tract from progressive emphysematous
changes has not been evaluated. Although the maintenance of blood serum
levels of α1-PI (antigenically measured) above 11 µM has been
historically postulated to provide therapeutically relevant
anti-neutrophil elastase protection, this has not been proven.
Individuals with severe α1-PI deficiency have been shown to
have increased neutrophil and neutrophil elastase concentrations in lung
epithelial lining fluid compared to normal PiMM individuals, and some
PiSZ individuals with α1-PI above 11 µM have emphysema
attributed to α1-PI deficiency. These observations underscore
the uncertainty regarding the appropriate therapeutic target serum level
of α1-PI during augmentation therapy. The clinical benefit of
the increased blood levels of Alpha1-Proteinase Inhibitor at the
recommended dose has not been established.
The clinical efficacy of ARALAST NP in influencing the course of
pulmonary emphysema or the frequency, duration, or severity of pulmonary
exacerbations has not been demonstrated in randomized, controlled
clinical trials.
Pharmacokinetics
The pharmacokinetics of ARALAST NP were compared with
ARALAST in a multicenter, single-dose, randomized, double-blind,
crossover clinical study (Study 460501). Twenty-five subjects
with congenital α1-PI deficiency received a single
intravenous (IV) infusion of 60 mg/kg ARALAST NP or ARALAST. The
25 subjects in this study were between 20 and 75 years old, with
a median age of 59. Plasma α1-PI concentrations were
measured using an enzyme linked immunosorbent assay (ELISA).
Figure 1 shows that the mean ± standard deviation (SD) plasma
α1-PI concentration-time profiles after a single
IV infusion of ARALAST NP and ARALAST at 60 mg/kg were
comparable. Table 2 summarizes the pharmacokinetic
parameters of ARALAST NP and ARALAST. The 90% confidence
intervals for Cmax and AUC 0 inf/dose were
well within the pre-defined acceptance limits of 80 to 125%.
Table 2:
Mean (± SD) Pharmacokinetic Parameters of ARALAST NP and
ARALAST Following a Single IV infusion of 60 mg/kg (n=25)
Parameters
|
Units
|
Aralast NP
|
Aralast
|
Cmax
|
mg/mL |
1.6 ± 0.3 |
1.7 ± 0.3 |
AUC0-inf/dose |
days*kg/mL |
0.0868 ± 0.0253 |
0.0920 ± 0.0238 |
Half-life |
days |
4.7 ± 2.7 |
4.8 ± 2.0 |
Clearance |
mL/day |
940 ± 275 |
862 ± 206 |
Vss
|
mL |
5632 ± 2006 |
5618 ± 1618 |
Cmax = Maximum increase in plasma
α1-PI concentration following
infusion; AUC0-inf/dose = Area under
the curve from time 0 to infinity divided by dose;
Half life = terminal phase half-life determined
using non-compartmental method; Vss =
Volume of distribution at steady state. |
A clinical study (ATC 97-01) was conducted to compare
ARALAST to a commercially available preparation of
α1–PI (Prolastin®, manufactured by Bayer
Corporation). All subjects were to have been diagnosed as having
congenital α1–PI deficiency and emphysema but no
α1–PI augmentation therapy within the preceding
six months.
Twenty-eight subjects were randomized to receive either
ARALAST or Prolastin®, 60 mg/kg intravenously per
week, for 10 consecutive weeks. Two subjects withdrew from the
study prematurely: 1 subject receiving ARALAST withdrew consent
after 6 infusions; 1 subject receiving Prolastin®
withdrew after 1 infusion due to pneumonia following unscheduled
bronchoscopy to remove a foreign body. Trough levels of
α1–PI (antigenic determination) and anti–NE
capacity (functional determination) were measured prior to
treatment at Weeks 8 through 11. Following their first 10 weekly
infusions, the subjects who were receiving Prolastin®
were switched to ARALAST while those who already were receiving
ARALAST continued to receive it. Maintenance of mean serum
α1–PI trough levels was assessed prior to
treatments at Weeks 12 through 24. Bronchoalveolar lavages
(BALs) were performed on subjects at baseline and prior to
treatment at Week 7. The epithelial lining fluid (ELF) from each
BAL meeting acceptance criteria was analyzed for the
α1–PI level and anti–NE capacity.
With weekly augmentation therapy with ARALAST or
Prolastin®, a gradual increase in peak and trough
serum α1–PI levels was noted, with stabilization
after several weeks. The metabolic half–life of ARALAST was 5.9
days. Serum anti–NE capacity trough levels rose substantially in
all subjects by Week 2, and by Week 3, serum anti–NE capacity
trough levels exceeded 11 µM in the majority of subjects. With
few exceptions, levels remained above this recommended threshold
level in individual subjects for the duration of the period
Weeks 3 through 24 on study. Although only five of fourteen
subjects (35.7%) receiving ARALAST had BALs meeting acceptance
criteria for analysis at both baseline and Week 7, a
statistically significant increase in the antigenic level of
α1–PI in the ELF was observed. No statistically
significant increase in the anti-NE capacity in the ELF was
detected.
Viral serology of all subjects was determined
periodically throughout the study, including testing for
antibodies to hepatitis A (HAV) and C (HCV), presence of
circulating HBsAg, and presence of antibodies to HIV–1, HIV–2,
and Parvovirus B–19. Subjects who were seronegative to
parvovirus B–19 at enrollment were retested by PCR at Week 2.
There were no seroconversions in subjects treated with ARALAST
through Week 24. None of the subjects became HBsAg positive
during the study, although five of 13 (38%) evaluable subjects
treated with ARALAST and eight of 13 (62%) treated with
Prolastin® had not been vaccinated to hepatitis
B. No patient developed antibodies against
α1–PI.
It was concluded that at a dose of 60 mg/kg administered
intravenously once weekly, ARALAST and Prolastin® had
similar effects in maintaining target serum α1–PI
trough levels and increasing antigenic levels of
α1–PI in epithelial lining fluid (ELF) with
maintenance augmentation therapy.
|