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Aralast ( Alpha 1-Antitrypsin) - Description and Clinical Pharmacology

 
 



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 1
Solvent Detergent-treatment > 5.8 > 6.0 > 5.5 N/A 2 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)

1 reduction factors ≤1.0 are not used for calculation of the overall reduction factor
2 Not applicable; study did not test for virus indicated

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.

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