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

 
 



DESCRIPTION

Alpha1-Proteinase Inhibitor (Human), Aralast™, is a sterile, stable, lyophilized preparation of purified human alpha1-proteinase inhibitor ((alpha) 1-PI), also known as alpha1-antitrypsin. 1

Aralast™ is prepared from large pools of human plasma by using the Cohn-Oncley cold alcohol fractionation process, followed by purification steps including polyethylene glycol and zinc chloride precipitations and ion exchange chromatography. To reduce the risk of viral transmission, the manufacturing process includes treatment with a solvent detergent (SD) mixture [tri-n-butyl phosphate and polysorbate 80] to inactivate enveloped viral agents such as HIV and Hepatitis B and C. In addition, a nanofiltration step is incorporated prior to final sterile filtration to reduce the risk of transmission of non-enveloped viral agents. Based on in vitro studies, the process used to produce Aralast™ has been shown to inactivate and/or partition various viruses as shown in the table below. 2

Processing Step Elimination of Deliberately Added Virus (Number of logs inactivated/removed)
HIV-1 * BVD **/* PRV **/* HAV # PPV #
Alcohol Fractionation >/= 4.8 N/A N/A N/A N/A
Solvent Detergent Treatment >/= 7.2 >/= 4.8 >/= 5.1 N/A N/A
Nanofiltration N/A >/= 6.0 >/= 5.5 8.6 >/= 5.8
Accumulated Reduction >/= 12.0 >/= 10.8 >/= 10.6 8.6 >/= 5.8
*HIV-1: Fractionation units log10 SFU SD Treatment units log10 TCID50/mL
**/* BVD (Bovine Viral Diarrhea), PRV (Pseudorables Virus): SD Treatment units log10 PFU/mL, Nanofiltration units log10 PFU
# HAV (Hepatitis A), PPV (Porcine Parvovirus) Nanofiltration units log10 PFU
N/A Not Applicable

When reconstituted as directed, the concentration of (alpha)1-PI is not less than 16 mg/mL and the specific activity is not less than 0.55 mg active (alpha)1-PI/mg total protein. The composition of the reconstituted product is as follows:

Component Quantity/mL
Elastase Inhibitory Activity NLT 400 mg Active (alpha)1-PI/0.5 g vial *
NLT 800 mg Active (alpha)1-PI/1.0 g vial **
Albumin NMT 5 mg/mL
Polyethylene Glycol NMT 112 µg/mL
Polysorbate 80 NMT 50 µg/mL
Sodium NMT 230 mEq/L
Tri-n-butyl Phosphate NMT 1.0 µg/mL
Zinc NMT 3 ppm
NLT: Not Less Than
NMT: Not More Than
*Reconstitution volume: 25 mL/0.5 g vial
**Reconstitution volume: 50 mL/1.0 g vial

Each vial of Aralast™ is labeled with the amount of functionally active (alpha)1-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

Alpha1-Proteinase Inhibitor (Human), Aralast™, 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, (alpha)1-PI is thought to provide more than 90% of the anti-NE protection in the lower respiratory tract.3,4

(alpha)1-PI deficiency is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of (alpha)1-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. 1,3,4,6-8 Individuals with (alpha)1-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.7 The emphysema associated with (alpha)1-PI deficiency is typically worse in the lower lung zones5. It is believed to develop because there are insufficient amounts of (alpha)1-PI in the lower respiratory tract to inhibit NE. This imbalance allows unopposed destruction of the connective tissue framework of the lung parenchyma.7,8

There are a large number of phenotypic variants of this disorder.1,3,4 Individuals with the PiZZ variant typically have serum (alpha)1-PI levels less than 35% of the average normal level.1,5 Individuals with the Pi(null)(null) variant have undetectable (alpha)1-PI protein in their serum.1,3 Individuals with these low serum (alpha)1-PI levels, i.e., less than 11 [micro ]molar (80 mg/dL), have an unknown risk of developing emphysema over their lifetimes. Two Registry studies have shown risks of 54.2 and 57.0%. 1,3,9 The risk of accelerated development and progression of emphysema in individuals with severe (alpha)1-PI deficiency is higher in smokers than in ex-smokers or non-smokers. 3. The deficiency in (alpha)1-PI represents one of the most common, potentially lethal hereditary disorders. 4

A clinical study was conducted to compare Aralast™ (test drug) to a commercially available preparation of (alpha)1-PI (Prolastin®), manufactured by Bayer Corporation. All subjects were to have been diagnosed as having congenital (alpha)1-PI deficiency and emphysema but no (alpha)1-PI augmentation therapy within the preceding six months.

Twenty-eight subjects were randomized to receive either test drug or control drug, 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 serum (alpha)1-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 control drug were switched to Aralast™ while those who already were receiving Aralast™ continued to receive it. Maintenance of mean serum (alpha)1-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 ELF from each BAL meeting acceptance criteria was analyzed for the (alpha)1-PI level and anti-NE capacity.

With weekly augmentation therapy, a gradual increase in peak and trough serum (alpha)1-PI levels was noted, with stabilization after several weeks. The metabolic half-life of Alpha1-Proteinase Inhibitor (Human), 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 [micro ]M 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 (alpha)1-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 in the test group and eight of 13 (62%) in the control group had not been vaccinated to hepatitis B. No patient developed antibodies against (alpha)1-PI.

It was concluded that at a dose of 60 mg/kg administered intravenously once weekly, Aralast™ and the control (alpha)1-PI preparation had similar effects in maintaining target serum (alpha)1-PI trough levels and increasing antigenic levels of (alpha)1-PI in epithelial lining fluid (ELF) with maintenance augmentation therapy.

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