Alfa1 antitrypsin Other names: α1-antitrypsin Serpin family A member 1 Alpha1 proteinase inhibitor A1PI A1AT

Alpha₁-antitrypsin is understood to be the primary anti-protease in the lower respiratory tract, where it inhibits neutrophil elastase (NE). Normal healthy individuals produce sufficient alpha₁-antitrypsin to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of lung tissue by NE. Conditions that increase neutrophil accumulation and activation in the lung, such as respiratory infection and smoking, will in turn increase levels of NE. However, individuals deficient in endogenous alpha₁-antitrypsin are unable to maintain appropriate antiprotease defence and experience more rapid proteolysis of the alveolar walls starting prior to the development of clinically evident chronic obstructive lung disease in the third or fourth decade.

Alpha₁-antitrypsin is a normal constituent of human blood. Human alpha₁-antitrypsin has a molecular weight of 51 kDa and belongs to the family of serine protease inhibitors.

Pharmacodynamic effects

The administration of alpha₁-antitrypsin increases and maintains serum levels and lung epithelial lining fluid (ELF) levels of alpha₁-antitrypsin leading to a slowdown of the progression of emphysema.

Four clinical studies were conducted with alpha₁-antitrypsin in 89 subjects (59 males and 30 females) to evaluate the effect on serum levels of alpha₁-antitrypsin. The subjects ranged in age from 29 to 68 years (median age 49 years). At screening, serum alpha₁-antitrypsin levels were between 3.2 and 10.1 µM (mean of 5.6 µM).

A double-blind, randomized, active-controlled, crossover pharmacokinetic study was conducted in 13 males and 5 females with alpha₁-antitrypsin deficiency, ranging in age from 36 to 66 years. Nine subjects received a single 60 mg/kg bw dose of alpha₁-antitrypsin followed by a comparator product, and 9 subjects received comparator product followed by a single 60 mg/kg bw dose of alpha₁-antitrypsin, with a wash-out period of 35 days between doses. A total of 13 post-infusion serum samples were taken at various time points up to Day 21. Table 1 shows the mean results for the alpha₁-antitrypsin pharmacokinetic parameters.

Table 1. Pharmacokinetic parameters for alpha₁-antitrypsin following a single 60 mg/kg bw dose:

* n=18 subjects.

A population pharmacokinetic analysis was conducted using data from 90 alpha₁-antitrypsin-treated subjects from the RAPID trial. The population estimate of mean half-life was 6.8 days. The model predicted mean steady-state concentration was 21.8 µM after a 60 mg/kg bw / week dose. The population pharmacokinetic analysis did not indicate that there were any significant effects of age, gender, weight, or baseline serum antigenic alpha₁-antitrypsin concentrations on the clearance of alpha₁ antitrypsin.

Pharmacokinetic/pharmacodynamic relationship

In a double-blind, controlled clinical study to evaluate the safety and biochemical efficacy of alpha₁-antitrypsin 44 subjects were randomized to receive 60 mg/kg bw intravenous dose of alpha₁-antitrypsin once weekly for 24 weeks. The mean trough serum alpha₁-antitrypsin levels at steady state (Weeks 7-11) were maintained above 11 µM. The mean (Standard Deviation) of the steady state trough serum alpha₁-antitrypsin level for alpha₁-antitrypsin-treated subjects was 17.7 µM (2.5). In a subgroup of subjects enrolled in this study (10 alpha₁ antitrypsin-treated subjects) broncho-alveolar lavage was performed. Epithelial lining fluid measurements (ELF) of alpha₁-antitrypsin levels showed a consistent increase following treatment. ELF levels of antigenic alpha₁-antitrypsin and alpha₁-antitrypsin: NE complexes increased from baseline. Free elastase was immeasurably low in all samples.

Following the completion of the RAPID study, an analysis of achieved median alpha₁-antitrypsin levels and lung density decline was conducted. This analysis revealed an inverse linear relationship between trough serum alpha₁-antitrypsin levels and the annual decline in lung density as measured by volume adjusted CT scans for subjects receiving 60 mg/kg bw intravenous dose of alpha₁-antitrypsin.

The safety of alpha₁-antitrypsin has been assessed in several preclinical studies. Non-clinical data reveal no special risk for humans based on safety pharmacology and short term toxicity studies. Repeat dose toxicity studies longer than 5 days, reproductive toxicity studies and carcinogenicity studies, have not been performed. Such studies are not considered meaningful due to the production of antibodies against the heterologous human protein in animals. Since human alpha₁-antitrypsin is a protein and a physiological constituent of human blood, it is not expected to present carcinogenic, genotoxic, or teratogenic effects.