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

 
 



DESCRIPTION

Alpha1-Proteinase Inhibitor (Human), Prolastin® is a sterile, stable, lyophilized preparation of purified human Alpha1-Proteinase Inhibitor (alpha1-PI), also known as alpha1-antitrypsin. Prolastin is intended for use in therapy of congenital alpha1-antitrypsin deficiency.

Prolastin is prepared from pooled human plasma of normal donors by modification and refinements of the cold ethanol method of Cohn. 1 Part of the fractionation may be performed by another licensed manufacturer. In order to reduce the potential risk of transmission of infectious agents, Prolastin has been heat-treated in solution at 60±0.5°C for not less than 10 hours. However, no procedure has been found to be totally effective in removing viral infectivity from plasma fractionation products. In vitro studies designed to evaluate the capacity of the Prolastin manufacturing process to remove/inactivate viruses have been conducted to provide additional assurance of the viral safety profile as shown in the table below.

Process Step Log10 Virus Reduction
  HIV-1 * BVDV ** PRV *** Reo **/* HAV # PPV &
Fractionation of
Effluent I to II + III
3.4 3.5 3.9 2.1 1.4 1.0
PEG Precipitation 4.4 3.2 3.4 3.4 3.1 3.3
Depth Filtration >/=4.7 4.1 >/=4.7 >/=4.0 >/=2.8 >/=4.3
Pasteurization >/=6.3 4.8 >/=4.8 N/A N/A N/A
Accumulated Log10
Reduction
>/=18.8 15.6 >/=16.8 >/=9.5 >/=7.3 >/=8.6
*Human immunodeficiency virus, type 1
** Bovine viral diarrhea virus (BVDV) was chosen to model hepatitis C virus
*** Pseudorabies virus (PRV) was used as a surrogate for hepatitis B virus and the human herpes viruses
**/* Reovirus type 3 (Reo) was chosen to model non-enveloped viruses
# Human hepatitis A virus (HAV).
& Porcine parvovirus (PPV) was selected as a surrogate for human parvovirus B19

The specific activity of Prolastin is >/=0.35 mg functional alpha1-PI/mg protein and when reconstituted as directed, the concentration of alpha1-PI is >/=20 mg/mL. When reconstituted, Prolastin has a pH of 6.6-7.4, a sodium content of 100-210 mEq/L, a chloride content of 60-180 mEq/L, a sodium phosphate content of 0.015-0.025 M, a polyethylene glycol content of not more than (NMT) 5 ppm, and NMT 0.1% sucrose. Prolastin contains small amounts of other plasma proteins including alpha2-plasmin inhibitor, alpha1-antichymotrypsin, C1-esterase inhibitor, haptoglobin, antithrombin III, alpha1-lipoprotein, albumin, and IgA. 1

Each vial of Prolastin contains the labeled amount of functionally active alpha1-PI in milligrams per vial (mg/vial), as determined by capacity to neutralize porcine pancreatic elastase. 1 Prolastin contains no preservative and must be administered by the intravenous route.

CLINICAL PHARMACOLOGY

Alpha1-antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alpha1-PI (alpha1-antitrypsin) is associated with slowly progressive, severe panacinar emphysema that most often manifests itself in the third to fourth decades of life. 2-9 [Although the terms "Alpha1-Proteinase Inhibitor" and "alpha1-antitrypsin" are used interchangeably in the scientific literature, the hereditary disorder associated with a reduction in the serum level of alpha1-PI is conventionally referred to as "alpha1-antitrypsin deficiency" while the deficient protein is referred to as "Alpha1-Proteinase Inhibitor" 10 ]. The emphysema is typically worse in the lower lung zones. 4, 8, 9 The pathogenesis of development of emphysema in alpha1-antitrypsin deficiency is not well understood at this time. It is believed, however, to be due to a chronic biochemical imbalance between elastase (an enzyme capable of degrading elastin tissues, released by inflammatory cells, primarily neutrophils, in the lower respiratory tract) and alpha1-PI (the principal inhibitor of neutrophil elastase), which is deficient in alpha1-antitrypsin disease. 11 -15 As a result, it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic, low-level burden of neutrophils in the lower respiratory tract, resulting in progressive degradation of elastin tissues. 11 -15 The eventual outcome is the development of emphysema. Neonatal hepatitis with cholestatic jaundice appears in approximately 10% of newborns with alpha1-antitrypsin deficiency. 15 In some adults, alpha1-antitrypsin deficiency is complicated by cirrhosis. 15

A large number of phenotypic variants of alpha1-antitrypsin deficiency exists. 15 The most severely affected individuals are those with the PiZZ variant, typically characterized by alpha1-PI serum levels <35% normal. 15 Epidemiologic studies of individuals with various phenotypes of alpha1-antitrypsin deficiency have demonstrated that individuals with endogenous serum levels of alpha1-PI </=50 mg/dL (based on commercial standards) have a risk of >80% of developing emphysema over a lifetime. 3 -6,8,9,16 However, individuals with endogenous alpha1-PI levels >80 mg/dL, in general, do not manifest an increased risk for development of emphysema above the general population background risk. 5, 15 From these observations, it is believed that the "threshold" level of alpha1-PI in the serum required to provide adequate anti-elastase activity in the lung of individuals with alpha1-antitrypsin deficiency is about 80 mg/dL (based on commercial standards for immunologic assay of alpha1-PI). 12, 15, 17

In clinical studies of Alpha1-Proteinase Inhibitor (Human), Prolastin®, 23 subjects with the PiZZ variant of congenital deficiency of alpha1-antitrypsin deficiency and documented destructive lung disease participated in a study of acute and/or chronic replacement therapy with Prolastin. 18 The mean in vivo recovery of alpha1-PI was 4.2 mg (immunologic)/dL per mg (functional)/kg body weight administered. 18, 19 The half-life of alpha1-PI in vivo was approximately 4.5 days. 18, 19 Based on these observations, a program of chronic replacement therapy was developed. Nineteen of the subjects in these studies received Prolastin replacement therapy, 60 mg/kg body weight, once weekly for up to 26 weeks (average 24 weeks of therapy). With this schedule of replacement therapy, blood levels of alpha1-PI were maintained above 80 mg/dL (based on the commercial standards for alpha1-PI immunologic assay). 18-20 Within a few weeks of commencing this program, bronchoalveolar lavage studies demonstrated significantly increased levels of alpha1-PI and functional antineutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing the program of chronic replacement therapy with Alpha1-Proteinase Inhibitor (Human), Prolastin®. 18-20

All 23 individuals who participated in the investigations were immunized with Hepatitis B Vaccine and received a single dose of Hepatitis B Immune Globulin (Human) on entry into the investigation. Although no other steps were taken to prevent hepatitis, neither hepatitis B nor non-A, non-B hepatitis occurred in any of the subjects. 18, 19 All subjects remained seronegative for HIV antibody. None of the subjects developed any detectable antibody to alpha1-PI or other serum protein.

Long-term controlled clinical trials to evaluate the effect of chronic replacement therapy with Prolastin on the development of or progression of emphysema in patients with congenital alpha1-antitrypsin deficiency have not been performed. Estimates of the sample size required of this rare disorder and the slow, progressive nature of the clinical course have been considered impediments in the ability to conduct such a trial. 21 Studies to monitor the long-term effects will continue as part of the postapproval process.

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