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Mechanism Of Action
A1-PI deficiency is a chronic, hereditary, autosomal, co-dominant disorder that is usually fatal in its severe form. Low blood levels of A1-PI (i.e., below 11 μM) are most commonly associated with progressive, severe emphysema that becomes clinically apparent by the third to fourth decade of life. In addition, PiSZ individuals, whose serum A1-PI levels range from approximately 9 to 23 mM, are considered to have a moderately increased risk for developing emphysema, regardless of whether their serum A1-PI levels are above or below 11 mM.2 Not all individuals with severe genetic variants of A1-PI deficiency have emphysema. Augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe congenital A1-PI deficiency who have clinically evident emphysema. A registry study showed 54% of A1-PI deficient subjects had emphysema.3 Another registry study showed 72% of A1-PI deficient subjects had pulmonary symptoms.4 Smoking is an important risk factor for the development of emphysema in patients with A1-PI deficiency.
Approximately 100 genetic variants of A1-PI deficiency can be identified electrophoretically, only some of which are associated with the clinical disease.5,6 Ninety-five percent of clinically symptomatic A1-PI deficient individuals are of the severe PiZZ phenotype. Up to 39% of A1-PI deficient patients may have an asthmatic component to their lung disease, as evidenced by symptoms and/or bronchial hyperreactivity.3 Pulmonary infections, including pneumonia and acute bronchitis, are common in A1-PI deficient patients and contribute significantly to the morbidity of the disease.
Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with A1-PI deficiency. However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical studies. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between NE and protease inhibitors.
Whether augmentation therapy with Zemaira or any A1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been evaluated. Individuals with endogenous levels of A1-PI below 11 mM, in general, manifest a significantly increased risk for development of emphysema above the general population background risk.6,7,8,9 Although the maintenance of blood serum levels of A1-PI (antigenically measured) above 11 mM has been historically postulated to provide therapeutically relevant antineutrophil elastase protection10, this has not been proven. Individuals with severe A1-PI deficiency have been shown to have increased neutrophil and NE concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with A1-PI above 11 mM have emphysema attributed to A1-PI deficiency.2 These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of A1- PI during augmentation therapy.
Pulmonary disease, particularly emphysema, is the most frequent manifestation of A1-PI deficiency.6 The pathogenesis of emphysema is understood to evolve as described in the “protease-antiprotease imbalance” model. A1-PI is now understood to be the primary antiprotease in the lower respiratory tract, where it inhibits NE.11 Normal healthy individuals produce sufficient A1-PI 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 who are severelydeficient in endogenous A1-PI are unable to maintain an appropriate antiprotease defense and are thereby subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. Zemaira serves as A1-PI augmentation therapy in this patient population, acting to increase and maintain serum levels and (ELF) levels of A1-PI.
Weekly repeated infusions of A1-PI at a dose of 60 mg/kg lead to serum A1-PI levels above the historical target threshold of 11 mM.
The clinical benefit of the increased blood levels of A1-PI at the recommended dose has not been established for any A1-PI product.
A double-blind, randomized, active-controlled, crossover pharmacokinetic study was conducted in 13 males and 5 females with A1-PI deficiency, ranging in age from 36 to 66 years. Nine subjects received a single 60 mg/kg dose of Zemaira followed by Prolastin, and 9 subjects received Prolastin followed by a single 60 mg/kg dose of Zemaira, with a washout 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 6 shows the mean results for the Zemaira pharmacokinetic parameters.
Table 6: Pharmacokinetic Parameters for Antigenic A1-PI
in 18 Subjects Following a Single 60 mg/kg Dose of Zemaira
|Pharmacokinetic Parameter||Mean (SD)*|
|Area under the curve (AUC0-∞)||144 (±27) μM x day|
|Maximum concentration (Cmax)||44.1 (±10.8) μM|
|Terminal half-life (t½β)||5.1 (±2.4) days|
|Total clearance||603 (±129) mL/day|
|Volume of distribution at steady state||3.8 (±1.3) L|
|* n=18 subjects.|
Animal Toxicology And/Or Pharmacology
In a safety pharmacology study, dogs were administered a 60 or 240 mg/kg intravenous dose of Zemaira. At the clinical dose of 60 mg/kg, no changes in cardiovascular and respiratory parameters or measured hematology, blood chemistry, or electrolyte parameters were attributed to the administration of Zemaira. A minor transient decrease in femoral resistance and increase in blood flow were observed after administration of the 240 mg/ kg dose.
In single-dose studies, mice and rats were administered a 0, 60, 240, or 600 mg/kg intravenous dose of Zemaira and observed twice daily for 15 days. No signs of toxicity were observed up to 240 mg/kg. Transient signs of distress were observed in male mice and in male and female rats after administration of the highest dose (600 mg/kg).
In repeat-dose toxicity studies, rats and rabbits received 0, 60, or 240 mg/kg intravenous doses of Zemaira once daily for 5 consecutive days. No treatment-related effects on clinical signs, body weight, hematology, coagulation, or urinalysis were observed in rats administered up to 240 mg/kg. No signs of toxicity were observed in rabbits administered 60 mg/kg. Changes in organ weights and minimal epidermal ulceration were observed in rabbits administered 240 mg/kg, but had no clinical effects.
The local tolerance of Zemaira was evaluated in rabbits following intravenous, perivenous,and intraarterial administration. No treatment-related local adverse reactions were observed.
Clinical trials were conducted pre-licensure with Zemaira in 89 subjects (59 males and 30 females). The subjects ranged in age from 29 to 68 years (median age 49 years). Ninety-seven percent of the treated subjects had the PiZZ phenotype of A1-PI deficiency, and 3% had the MMALTON phenotype. At screening, serum A1-PI levels were between 3.2 and 10.1 mM (mean of 5.6 mM). The objectives of the clinical trials were to demonstrate that Zemaira augments and maintains serum levels of A1-PI above 11 mM (80 mg/dL) and increases A1-PI levels in ELF of the lower lung.
In a double-blind, controlled clinical trial to evaluate the safety and efficacy of Zemaira, 44 subjects were randomized to receive 60 mg/kg of either Zemaira or Prolastin once weekly for 10 weeks. After 10 weeks, subjects in both groups received Zemaira for an additional 14 weeks. Subjects were followed for a total of 24 weeks to complete the safety evaluation [see ADVERSE REACTIONS]. The mean trough serum A1-PI levels at steady state (Weeks 7-11) in the Zemaira-treated subjects were statistically equivalent to those in the Prolastin-treated subjects within a range of ±3 mM. Both groups were maintained above 11 mM. The mean (range and standard deviation [SD]) of the steady state trough serum antigenic A1-PI level for Zemaira-treated subjects was 17.7 mM (range 13.9 to 23.2, SD 2.5) and for Prolastin-treated subjects was 19.1 mM (range 14.7 to 23.1, SD 2.2). The difference between the Zemaira and the Prolastin groups was not considered clinically significant and may be related to the higher specific activity of Zemaira.
In a subgroup of subjects enrolled in the trial (10 Zemaira-treated subjects and 5 Prolastintreated subjects), bronchoalveolar lavage was performed at baseline and at Week 11.Four A1-PI related analytes in ELF were measured: antigenic A1-PI, A1-PI:NE complexes, free NE, and functional A1-PI (ANEC). A blinded retrospective analysis, which revised the prospectively established acceptance criteria showed that within each treatment group, ELF levels of antigenic A1-PI and A1-PI:NE complexes increased from baseline to Week 11 (Table 7). Free elastase was immeasurably low in all samples. The post-treatment ANEC values in ELF were not significantly different between the Zemaira-treated and Prolastin-treated subjects (mean 1725 nM vs. 1418 nM). No conclusions can be drawn about changes of ANEC values in ELF during the trial period as baseline values in the Zemaira-treated subjects were unexpectedly high. No A1-PI analytes showed any clinically significant differences between the Zemaira and Prolastin treatment groups.
Table 7: Change in ELF From Baseline to Week 11 in a
|Analyte||Treatment||Mean Change From Baseline||90% CI|
|A1-PI (nM)||Zemaira*||1358.3||822.6 to 1894.0|
|Prolastin†||949.9||460.0 to 1439.7|
|ANEC (nM)||Zemaira||-588.1||-2032.3 to 856.1|
|Prolastin||497.5||-392.3 to 1387.2|
|A1-PI:NE Complexes (nM)||Zemaira||118.0||39.9 to 196.1|
|Prolastin||287.1||49.8 to 524.5|
|CI, confidence interval.
* n=10 subjects.
† n=5 subjects.
The clinical efficacy of Zemaira or any A1-PI product in influencing the course of pulmonary emphysema or pulmonary exacerbations has not been demonstrated in adequately powered, randomized, controlled clinical trials.
2. Turino GM, Barker AF, Brantly ML, et al. Clinical features of individuals with PI*SZ phenotype of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 1996;154:1718-1725.
3. Stoller JK, Brantly M, et al. Formation and current results of a patient-organized registry for α1-antitrypsin deficiency. Chest. 2000;118(3):843-848.
4. McElvaney NG, Stoller JK, et al. Baseline characteristics of enrollees in the National Heart, Lung, and Blood Institute Registry of α1-Antitrypsin Deficiency. Chest. 1997;111:394-403.
5. Crystal RG. α1-antitrypsin deficiency, emphysema, and liver disease; genetic basis and strategies for therapy. J Clin Invest. 1990;85:1343-1352.
6. World Health Organization. Alpha-1-antitrypsin deficiency; Report of a WHO Meeting. Geneva. 18-20 March 1996.
7. Eriksson S. Pulmonary emphysema and alpha1-antitrypsin deficiency. ACTA Med Scand. 1964;175(2):197-205.
8. Eriksson S. Studies in α1-antitrypsin deficiency. ACTA Med Scan Suppl. 1965;432:1-85.
9. Gadek JE, Crystal RG. α1-antitrypsin deficiency. In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al., eds. The Metabolic Basis of Inherited Disease. 5th ed. New York, NY: McGraw-Hill; 1983:1450-1467.
10. American Thoracic Society. Guidelines for the approach to the patient with severehereditary alpha-1-antitrypsin deficiency. Am Rev Respir Dis. 1989;140:1494-1497.
11. Gadek JE, Fells GA, Zimmerman RL, Rennard SI, Crystal RG. Antielastases of the human alveolar structures; implications for the protease-antiprotease theory of emphysema. J Clin Invest. 1981;68:889-898.
Last reviewed on RxList: 3/18/2016
This monograph has been modified to include the generic and brand name in many instances.
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