Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety. STUDY DESIGN AND METHODS: This was a prospective, randomized, open-label, crossover study. Twenty-four subjects with mild or moderate HAE were randomly assigned during an attack-free interval to receive 1000 units of human pasteurized C1-INH concentrate IV or SC. Plasma levels of C1-INH activity and antigen, C4 antigen, cleaved high-molecular-weight kininogen (clHK), and C1-INH antibodies were measured. RESULTS: The mean relative bioavailability of functional C1-INH after SC administration was 39.7%. Maximum C1-INH activity after SC administration occurred within 48 hours and persisted longer than after IV administration. C4 antigen levels increased and clHK levels decreased after IV and SC administration, indicating the pharmacodynamic action of C1-INH. The mean half-life of functional C1-INH was 62 hours after IV administration and 120 hours after SC administration (p=0.0595). C1-INH concentrate was safe and well tolerated when administered via both routes. As expected, SC administration resulted in a higher incidence of injection site reactions, all of which were mild. CONCLUSION: With a relative bioavailability of 39.7%, SC administration of human pasteurized C1-INH yields potentially clinically relevant and sustained plasma levels of C1-INH and is safe and well tolerated.

Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema.

BACKGROUND: C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE). STUDY DESIGN AND METHODS: Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT). RESULTS: The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes. CONCLUSION: As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.

Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1-inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1-INH). STUDY DESIGN AND METHODS: This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate. RESULTS: The median half-life of functional C1-INH plasma levels in pediatric patients receiving on-demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT. CONCLUSIONS: pC1-INH concentrate has a long median terminal elimination half-life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE.

Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate.

OBJECTIVE: The objective of the study was to investigate the rates and characteristics of hereditary angioedema (HAE) attacks associated with pregnancy, delivery, and the postpartum period and their treatment with C1 esterase inhibitor (INH) concentrate. STUDY DESIGN: This was an observational study including 22 women with type I HAE, with data collected before, during, and after 35 pregnancies (37 children) based on patient diaries, interviews, and case report forms. RESULTS: In 83% of pregnancies, attack rates increased during pregnancy; highest mean rates occurred in the second and third trimesters. C1-INH concentrate effectively controlled attacks and was safe for mothers and children. Low-plasma C1-INH activity during pregnancy tended to be associated with an increased chance of giving birth to a child with HAE. CONCLUSION: Increased attack rates during pregnancy in women with HAE are well controlled with C1-INH concentrate, indicating the clear benefit of integrating the availability of C1-INH concentrate into the management plan for these women during pregnancy and delivery.

On demand treatment and home therapy of hereditary angioedema in Germany - the Frankfurt experience.

BACKGROUND: Manifestation of acute edema in hereditary angioedema (HAE) is characterized by interindividual and intraindividual variability in symptom expression over time. Flexible therapy options are needed. METHODS: We describe and report on the outcomes of the highly individualized approach to HAE therapy practiced at our HAE center in Frankfurt (Germany). RESULTS: The HAE center at the Frankfurt University Hospital currently treats 450 adults with HAE or AAE and 107 pediatric HAE patients with highly individualized therapeutic approaches. 73.9% of the adult patients treat HAE attacks by on-demand therapy with pasteurized pd C1-INH concentrate, 9.8% use additional prophylaxis with attenuated androgens, 1% of the total patient population in Frankfurt has been treated with Icatibant up to now. In addition adult and selected pediatric patients with a high frequency of severe attacks are instructed to apply individual replacement therapy (IRT) with pasteurized pd C1-INH concentrate. Improvement on Quality of Life items was shown for these patients compared to previous long-term danazol prophylaxis. Home treatment of HAE patients was developed in the Frankfurt HAE center in line with experiences in hemophilia therapy and has so far been implemented over a period of 28 years. At present 248 (55%) of the adult patients and 26 (24%) of the pediatric patients are practicing home treatment either as on demand or IRT treatment. CONCLUSIONS: In conclusion, the individualized home therapies provided by our HAE center, aim to limit the disruption to normal daily activities that occurs for many HAE patients. Furthermore, we seek to optimize the economic burden of the disease while offering a maximum quality of life to our patients.

C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis.

BACKGROUND: Hereditary angioedema (HAE) caused by functional deficiency of C1-inhibitor (C1-INH) is a rare disease that manifests with recurrent spontaneous nonallergic edema of the subcutaneous tissues and mucous membranes. In cases of laryngeal edema that are not treated immediately, HAE is associated with high mortality rates. Attenuated androgens (e.g., danazol) are usually administered for prophylaxis, but associated side effects may limit their use. This study investigated the efficacy, safety, and quality of life (QoL) associated with a pasteurized plasma-derived C1-inhibitor (pC1-INH) concentrate for individual replacement therapy (IRT) in patients with severe HAE suffering from frequent attacks who were intolerant or not responding to danazol. STUDY DESIGN AND METHODS: Twenty-two patients with severe HAE and danazol incompatibility or insufficient efficacy of danazol were recruited. Intraindividual comparisons of efficacy, safety, and QoL with pC1-INH concentrate IRT versus danazol treatment were made using retrospective and prospective patient data. Pharmacokinetic data were collected for 15 of the 22 patients. RESULTS: In patients receiving pC1-INH regularly, the median number of attacks per year decreased significantly compared to danazol prophylaxis (p < 0.001), and the 24 laryngeal edema episodes per year ceased. Superior efficacy of pC1-INH was found for all QoL variables (e.g., general condition, social activities). No transmission of human immunodeficiency virus or hepatitis A, B, or C was observed. CONCLUSION: In patients with severe HAE who experience severe side effects and/or lack of efficacy of danazol prophylaxis, very early substitution with pC1-INH can completely abolish the incidence of potentially fatal laryngeal edema and can reduce the incidence of acute attacks.

Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.

BACKGROUND: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) in 2004. OBJECTIVE: To ensure that this consensus remains current. METHODS: In collaboration with the Canadian Network of Rare Blood Disorder Organizations, we held the second Canadian Consensus discussion with our international colleagues in Toronto, Ontario, on February 3, 2006, and reviewed its content at the Fifth C1 Inhibitor Deficiency Workshop in Budapest on June 2, 2007. Papers were presented by international investigators, and this consensus algorithm approach resulted. RESULTS: This consensus algorithm outlines the approach recommended for the diagnosis, therapy, and management of HAE, which was agreed on by the authors of this report. This document is only a consensus algorithm approach and continues to require validation. As such, participants agreed to make this a living 2007 algorithm, a work in progress, and to review its content at future international HAE meetings. CONCLUSIONS: There is a paucity of double-blind, placebo-controlled trials on the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Controlled trials currently under way will provide further insight into the management of HAE. As with our Canadian 2003 Consensus, this 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE was formed through the meeting and agreement of patient care professionals along with patient group representatives and individual patients.

Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.

Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.