Antitrypsin deficiency · 5: Intravenous augmentation therapy: current understanding
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1 Division of Medicine, Section of Respiratory Therapy, Cleveland Clinic Lerner School of Medicine, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
2 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland OH 44195, USA
Correspondence to:
Dr J K Stoller
Division of Medicine, Section of Respiratory Therapy, Cleveland Clinic Lerner School of Medicine, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; stollej@ccf.org
ABSTRACT
The biochemical and clinical efficacy of intravenous augmentation therapy in 1-antitrypsin deficiency is reviewed, adverse events experienced with this treatment are considered, and its cost effectiveness is discussed.
Keywords: 1-antitrypsin deficiency; augmentation therapy
Because unopposed elastolysis is thought to be the mechanism by which emphysema develops in individuals with severe deficiency of 1-antitrypsin (AAT), the mainstay of current specific treatment for AAT deficiency is intravenous administration of purified AAT, so-called intravenous augmentation therapy. Pooled human plasma AAT has been licensed for prescription in several countries including the US, Canada, Italy, and Spain. This paper reviews the rationale for intravenous augmentation therapy and current evidence regarding its biochemical and clinical efficacy. After reviewing the specific criteria by which the biochemical and clinical efficacy of augmentation therapy can be judged, we then consider the available relevant studies that address efficacy. We also review the available data on adverse events experienced with augmentation therapy and its cost effectiveness, again by analysing the methodological features of available reports.
CRITERIA FOR DEMONSTRATING EFFICACY OF AUGMENTATION THERAPY
Criteria that must be satisfied in order to deem intravenous augmentation therapy effective should consider both the biochemical and clinical effects.1 Those for biochemical efficacy include:
evidence that intravenous augmentation therapy raises serum levels above the protective threshold and does so over the entire interdose interval;
evidence that the functional capacity of infused pooled human plasma AAT to oppose neutrophil elastase is preserved after the drug is infused.
Beyond these biochemical considerations, criteria that must be satisfied to assure clinical efficacy include:
evidence that the intravenous infusion of augmentation therapy slows the progression of emphysema or confers other clinical benefits such as decreased morbidity or enhanced survival;
evidence that augmentation therapy can be administered safely.
In considering the available evidence regarding the biochemical efficacy of intravenous augmentation therapy, Wewers et al2 first showed that the intravenous infusion of pooled human plasma AAT at a dose of 60 mg/kg once weekly produced serum levels that generally exceeded the protective threshold over the full dosing interval. As shown in fig 1, serum levels in 21 PI*ZZ recipients rose quite steeply acutely after infusion (to >300 mg/dl) and pre-dose nadir levels generally exceeded 11 μM (or 80 mg/dl), a level deemed to be the protective threshold above which the risk of emphysema is felt to be minimal but below which the risk rises. Indeed, nadir serum levels of AAT tended to rise over serial infusions, militating against the development of blocking antibodies. Furthermore, infused AAT maintained its functional anti-elastase activity, both in the serum and in the epithelial lining fluid (ELF).
Figure 1 Serum levels of 1-antitrypsin 30 minutes, 2 days, 4 days and 7 days after intravenous administration of 60 mg/kg body weight 1-antitrypsin. Each symbol represents the serum level for an individual subject receiving augmentation therapy. Reproduced from Wewers et al2 with permission of the publisher.
Subsequent studies have examined the biochemical efficacy of intravenous augmentation therapy administered at intervals other than weekly.3,4 Barker et al3 examined the pharmacokinetics of bi-weekly infusions of pooled human plasma AAT at a dose of 120 mg/kg in 23 PI*ZZ recipients who received 10 infusions each. In contrast to the pharmacokinetics of weekly augmentation therapy, serum levels above the protective threshold level of 80 mg/dl were achieved but were not sustained over the entire 2 week dosing interval. In no patient did the level remain >80 mg/dl over the full 14 days. In 41% (9/22) the levels were above 80 mg/dl for 7 days. Bronchoalveolar lavage was performed in five patients and epithelial lining fluid levels correlated poorly with serum levels (r = 0.60). Forced expiratory volume in 1 second (FEV1) was unchanged (1.22 l) among the recipients over a 20 week follow up period.3
Given the preference of both clinicians and patients for less frequent dosing of intravenous medications, the administration of monthly augmentation therapy has also been examined. Hubbard et al4 administered 250 mg/kg purified AAT intravenously once a month for 12 months to nine subjects with severe AAT deficiency (serum AAT levels <35 mg/dl or approximately 5 μM). As with weekly infusions, the nadir serum levels rose gradually over time, so that by the 12th month serum levels exceeded 80 mg/dl for a mean of 25 days of the 28 day dosing interval. Serum antineutrophil elastase activity was preserved and also rose over time, and ELF levels of AAT averaged 2.5 μM at day 28, thereby exceeding the theoretical ELF protective threshold value. No significant change in lung function was observed in recipients over the 12 month study period.4
Since these early studies of the first available preparation (pooled human plasma AAT prepared by pasteurisation (Prolastin, Bayer, West Haven, CT, USA)), more recent studies have examined the biochemical profile of a different pooled human plasma AAT preparation that is purified using solvent detergent and nanofiltration techniques (Aralast, Baxter, Westlake Village, CA, USA).5 Using Prolastin as a comparator, the newer drug was evaluated in a four centre, randomised, double blind, controlled trial in which 13 subjects received each of the preparations for 11 weekly infusions (of 60 mg/kg), after which an open label follow up study with the new drug was conducted. As shown in fig 2, administration of this newer preparation satisfied equivalence criteria to the earlier approved preparation. Trough serum AAT levels at weeks 8–11 were similar with the new preparation (ratio 0.905 to comparator) and the slope of trough levels from weeks 12 to 24 did not exceed –0.1. No serious adverse events associated with the drug were observed. On the basis of this study, the new preparation received approval by the United States Food and Drug Administration (FDA) in December 2002.6 A third preparation (Zemaira, ZLB Behring) has since received US FDA approval.
345–51.(J K Stoller1 and L S Abou)
2 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland OH 44195, USA
Correspondence to:
Dr J K Stoller
Division of Medicine, Section of Respiratory Therapy, Cleveland Clinic Lerner School of Medicine, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; stollej@ccf.org
ABSTRACT
The biochemical and clinical efficacy of intravenous augmentation therapy in 1-antitrypsin deficiency is reviewed, adverse events experienced with this treatment are considered, and its cost effectiveness is discussed.
Keywords: 1-antitrypsin deficiency; augmentation therapy
Because unopposed elastolysis is thought to be the mechanism by which emphysema develops in individuals with severe deficiency of 1-antitrypsin (AAT), the mainstay of current specific treatment for AAT deficiency is intravenous administration of purified AAT, so-called intravenous augmentation therapy. Pooled human plasma AAT has been licensed for prescription in several countries including the US, Canada, Italy, and Spain. This paper reviews the rationale for intravenous augmentation therapy and current evidence regarding its biochemical and clinical efficacy. After reviewing the specific criteria by which the biochemical and clinical efficacy of augmentation therapy can be judged, we then consider the available relevant studies that address efficacy. We also review the available data on adverse events experienced with augmentation therapy and its cost effectiveness, again by analysing the methodological features of available reports.
CRITERIA FOR DEMONSTRATING EFFICACY OF AUGMENTATION THERAPY
Criteria that must be satisfied in order to deem intravenous augmentation therapy effective should consider both the biochemical and clinical effects.1 Those for biochemical efficacy include:
evidence that intravenous augmentation therapy raises serum levels above the protective threshold and does so over the entire interdose interval;
evidence that the functional capacity of infused pooled human plasma AAT to oppose neutrophil elastase is preserved after the drug is infused.
Beyond these biochemical considerations, criteria that must be satisfied to assure clinical efficacy include:
evidence that the intravenous infusion of augmentation therapy slows the progression of emphysema or confers other clinical benefits such as decreased morbidity or enhanced survival;
evidence that augmentation therapy can be administered safely.
In considering the available evidence regarding the biochemical efficacy of intravenous augmentation therapy, Wewers et al2 first showed that the intravenous infusion of pooled human plasma AAT at a dose of 60 mg/kg once weekly produced serum levels that generally exceeded the protective threshold over the full dosing interval. As shown in fig 1, serum levels in 21 PI*ZZ recipients rose quite steeply acutely after infusion (to >300 mg/dl) and pre-dose nadir levels generally exceeded 11 μM (or 80 mg/dl), a level deemed to be the protective threshold above which the risk of emphysema is felt to be minimal but below which the risk rises. Indeed, nadir serum levels of AAT tended to rise over serial infusions, militating against the development of blocking antibodies. Furthermore, infused AAT maintained its functional anti-elastase activity, both in the serum and in the epithelial lining fluid (ELF).
Figure 1 Serum levels of 1-antitrypsin 30 minutes, 2 days, 4 days and 7 days after intravenous administration of 60 mg/kg body weight 1-antitrypsin. Each symbol represents the serum level for an individual subject receiving augmentation therapy. Reproduced from Wewers et al2 with permission of the publisher.
Subsequent studies have examined the biochemical efficacy of intravenous augmentation therapy administered at intervals other than weekly.3,4 Barker et al3 examined the pharmacokinetics of bi-weekly infusions of pooled human plasma AAT at a dose of 120 mg/kg in 23 PI*ZZ recipients who received 10 infusions each. In contrast to the pharmacokinetics of weekly augmentation therapy, serum levels above the protective threshold level of 80 mg/dl were achieved but were not sustained over the entire 2 week dosing interval. In no patient did the level remain >80 mg/dl over the full 14 days. In 41% (9/22) the levels were above 80 mg/dl for 7 days. Bronchoalveolar lavage was performed in five patients and epithelial lining fluid levels correlated poorly with serum levels (r = 0.60). Forced expiratory volume in 1 second (FEV1) was unchanged (1.22 l) among the recipients over a 20 week follow up period.3
Given the preference of both clinicians and patients for less frequent dosing of intravenous medications, the administration of monthly augmentation therapy has also been examined. Hubbard et al4 administered 250 mg/kg purified AAT intravenously once a month for 12 months to nine subjects with severe AAT deficiency (serum AAT levels <35 mg/dl or approximately 5 μM). As with weekly infusions, the nadir serum levels rose gradually over time, so that by the 12th month serum levels exceeded 80 mg/dl for a mean of 25 days of the 28 day dosing interval. Serum antineutrophil elastase activity was preserved and also rose over time, and ELF levels of AAT averaged 2.5 μM at day 28, thereby exceeding the theoretical ELF protective threshold value. No significant change in lung function was observed in recipients over the 12 month study period.4
Since these early studies of the first available preparation (pooled human plasma AAT prepared by pasteurisation (Prolastin, Bayer, West Haven, CT, USA)), more recent studies have examined the biochemical profile of a different pooled human plasma AAT preparation that is purified using solvent detergent and nanofiltration techniques (Aralast, Baxter, Westlake Village, CA, USA).5 Using Prolastin as a comparator, the newer drug was evaluated in a four centre, randomised, double blind, controlled trial in which 13 subjects received each of the preparations for 11 weekly infusions (of 60 mg/kg), after which an open label follow up study with the new drug was conducted. As shown in fig 2, administration of this newer preparation satisfied equivalence criteria to the earlier approved preparation. Trough serum AAT levels at weeks 8–11 were similar with the new preparation (ratio 0.905 to comparator) and the slope of trough levels from weeks 12 to 24 did not exceed –0.1. No serious adverse events associated with the drug were observed. On the basis of this study, the new preparation received approval by the United States Food and Drug Administration (FDA) in December 2002.6 A third preparation (Zemaira, ZLB Behring) has since received US FDA approval.
345–51.(J K Stoller1 and L S Abou)