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Absolute Bioavailability of Subcutaneously Administered Icatibant, a Selective and Potent Bradykinin B2 Receptor Antagonist
S274 Abstracts
J ALLERGY CLIN IMMUNOL JANUARY 2007
1071
1073
1072
1074
Absolute Bioavailability of Subcutaneously Administered Icatibant, a Selective and Potent Bradykinin B2 Receptor Antagonist F. Wagner1, B. Rosenkranz2, J. Knolle2; 1Charite Research Organisation GmbH, Berlin, GERMANY, 2Jerini AG, Berlin, GERMANY. RATIONALE: This phase I study assessed the absolute bioavailability and tolerability of subcutaneous (SC) versus intravenous (IV) administration of Icatibant in healthy volunteers. METHODS: A total of 24 healthy males aged 18-50 years entered this single-centre study. Subjects received 0.4 mg/kg Icatibant IV (as a 1 mg/ml solution, for 30 min) or SC (as a 10 or 20 mg/ml solution) in an open-label crossover design. RESULTS: At a dose of 0.4 mg/kg, the mean absolute bioavailability (AUC0-N) for SC Icatibant was 96.1% (95% confidence interval [CI]: 86.7, 106.4) for the 10 mg/ml formulation, and 83.4% (95% CI: 70.9, 98.2) for 20 mg/ml. AUC0-inf values were comparable for SC (3114 and 2615 h*ng/ml, for 10 and 20 mg/ml, respectively) and IV (3208 h*ng/ ml) Icatibant. Mean Cmax values were 1429 ng/mL for the 10 mg/mL SC injection, 1149 ng/mL for the 20 mg/mL SC injection, and 2971 ng/mL for the IV infusion. Regardless of administration route or Icatibant concentration, Cmax was reached by approximately 0.5 h. Elimination half life (1.2-1.5 h) was similar for SC and IV administration. All adverse events were mild, and local site reactions usually resolved spontaneously within 1 h. There were no serious adverse events. Laboratory parameters, vital signs and ECG did not show relevant changes during the study. CONCLUSIONS: Bioavailability of Icatibant is similar for SC and IV administration routes. Icatibant was safe and well tolerated at the dose of 0.4 mg/kg. Funding: Jerini AG Successful Treatment of Chronic Idiopathic Urticaria & Angioedema (CIU), With Xolair (Omalizumab) C. A. Shapiro1, N. S. Kapetanos2, E. Sarmiento2; 1Flushing Hospital Med Ctr, Flushing, NY, 2Advanced Allergy & Asthma Assessment & Diagnostics, P.C., Bayside, NY. RATIONALE: Chronic idiopathic Urticaria is at times recalcitrant to published therapies. These include multiple antihistamines, oral steroids and in worst cases highly toxic immunosupressives. Other therapies that are not as toxic need to be explored. METHODS: 6 patients with severe hives with and without angioedema whom either failed or refused the use of immunosuppressives, after informed consent, were offered Xolair therapy. Dosages were based upon the PI sheet for treatment of asthma. The treatment interval was based upon reoccurrence of hives or angioedema. RESULTS: 5 of 6 patients had complete control of all symptoms and were able to eliminate most other medications within 1 week of the first dose. The 6th patient had no response. Most patients that were able to stop after 6 months have had no reoccurrences to date. CONCLUSIONS: Xolair therapy may show promise for the treatment of CIU and angioedema. The rapid control of symptoms may suggest an alternative mechanism of mast cell stabilization. Some patients may have no response to this therapy. The cost of therapy is close to that of a multiple antihistamine regiment. Controlled studies should be done in order considered to confirm our clinical findings.
Resolution of Angioedema with Omalizumab J. W. Blume, S. Kiratseavee, M. F. Sands; University at Buffalo, Buffalo, NY. RATIONALE: Omalizumab is a recombinant humanized monoclonal anti-IgE antibody FDA-approved for the treatment of moderate to severe persistent asthma. To date, there are no reports of improvement of angioedema with omalizumab. METHODS: We present a patient who experienced remission of recurrent idiopathic angioedema after omalizumab initiation. RESULTS: Our patient is a 65-year-old Caucasian male with a history of moderate persistent asthma and sarcoidosis who developed recurrent angioedema 8 years ago. He developed swelling in his feet, scrotum, face, tongue, and occasionally larynx twice weekly, requiring self-administered epinephrine, and ER visits and/or hospitalizations about twice monthly. He felt his angioedema may have been food-related, but dietary restriction of beef, peanuts, coffee, eggs, and chocolate was not beneficial. Angioedema persisted despite cessation of his ACE inhibitor and NSAIDS. Physical exam: unremarkable. Labs: CBC with differential, comprehensive metabolic panel, ANA, and TSH normal. IgE 244 (0-144 kU/L). C2 2.1 (1.64.0 mg/dL). C4 30 (16-47 mg/dL). C1 inhibitor 37 (21-39 mg/dL). C1 inhibitor function normal. C1q 16.2 (11.8-23.8 mg/dL). RAST positive to coffee (class 0/1), egg white (class 2), and beef (class 3). In November 2005, omalizumab was instituted for treatment of his asthma. Soon after omalizumab was initiatiated, the patient’s angioedema regressed. He currently remains asymptomatic. CONCLUSIONS: To our knowledge, we report the first case of control of idiopathic angioedema with omalizumab. This case suggests the need for a prospective trial of omalizumab in cases of refractory angioedema to determine possible efficacy (and mechanisms) for its utility as a therapeutic agent.
TUESDAY
Angioedema from Angiotensin I-Converting Enzyme Inhibitors May Have a Genetic Basis in AfricanAmerican Families A. Shah, D. Shats, V. Rajput; UMDNJ-Robert Wood Johnson Medical School. Cooper University Hospital, Camden, NJ. RATIONALE: Angioedema associated with angiotensin I-converting enzyme inhibitors (AE-ACEi) has a genetic predisposition. METHODS: We identify an African American female who presents with facial angioedema while on ACEi therapy. Further history reveals that her natural mother and sister had similar reactions to ACEi. We conducted a MEDLINE search of familial ACEi-associated angioedema using the keywords ‘‘angioedema,’’ ‘‘ACEi,’’ and ‘‘family history.’’ RESULTS: Twenty cases of AE-ACEi have been described within five Caucasian families with decreased aminopeptidase P (APP) activity associated with a variant in the XPNPEP2 gene. Currently there is no identification of a similar genetic variant in African-American families in the literature. Impaired bradykinin metabolism plays a central role in AEACEi. Bradykinin is degraded in the plasma by ACE and APP; however, lower plasma APP activity is reported in patients with AE-ACEi. APP activity is partially regulated by the gene XPNPEP2 in Caucasian families. CONCLUSIONS: AE-ACEi is a complex phenomenon largely modulated by genetic factors. Genes linked to APP activity appear to have a significant role in AE-ACEi and have been identified in Caucasian families. Further genetic research is needed in African-American families with AE-ACEi.
J ALLERGY CLIN IMMUNOL JANUARY 2007
1071
1073
1072
1074
Absolute Bioavailability of Subcutaneously Administered Icatibant, a Selective and Potent Bradykinin B2 Receptor Antagonist F. Wagner1, B. Rosenkranz2, J. Knolle2; 1Charite Research Organisation GmbH, Berlin, GERMANY, 2Jerini AG, Berlin, GERMANY. RATIONALE: This phase I study assessed the absolute bioavailability and tolerability of subcutaneous (SC) versus intravenous (IV) administration of Icatibant in healthy volunteers. METHODS: A total of 24 healthy males aged 18-50 years entered this single-centre study. Subjects received 0.4 mg/kg Icatibant IV (as a 1 mg/ml solution, for 30 min) or SC (as a 10 or 20 mg/ml solution) in an open-label crossover design. RESULTS: At a dose of 0.4 mg/kg, the mean absolute bioavailability (AUC0-N) for SC Icatibant was 96.1% (95% confidence interval [CI]: 86.7, 106.4) for the 10 mg/ml formulation, and 83.4% (95% CI: 70.9, 98.2) for 20 mg/ml. AUC0-inf values were comparable for SC (3114 and 2615 h*ng/ml, for 10 and 20 mg/ml, respectively) and IV (3208 h*ng/ ml) Icatibant. Mean Cmax values were 1429 ng/mL for the 10 mg/mL SC injection, 1149 ng/mL for the 20 mg/mL SC injection, and 2971 ng/mL for the IV infusion. Regardless of administration route or Icatibant concentration, Cmax was reached by approximately 0.5 h. Elimination half life (1.2-1.5 h) was similar for SC and IV administration. All adverse events were mild, and local site reactions usually resolved spontaneously within 1 h. There were no serious adverse events. Laboratory parameters, vital signs and ECG did not show relevant changes during the study. CONCLUSIONS: Bioavailability of Icatibant is similar for SC and IV administration routes. Icatibant was safe and well tolerated at the dose of 0.4 mg/kg. Funding: Jerini AG Successful Treatment of Chronic Idiopathic Urticaria & Angioedema (CIU), With Xolair (Omalizumab) C. A. Shapiro1, N. S. Kapetanos2, E. Sarmiento2; 1Flushing Hospital Med Ctr, Flushing, NY, 2Advanced Allergy & Asthma Assessment & Diagnostics, P.C., Bayside, NY. RATIONALE: Chronic idiopathic Urticaria is at times recalcitrant to published therapies. These include multiple antihistamines, oral steroids and in worst cases highly toxic immunosupressives. Other therapies that are not as toxic need to be explored. METHODS: 6 patients with severe hives with and without angioedema whom either failed or refused the use of immunosuppressives, after informed consent, were offered Xolair therapy. Dosages were based upon the PI sheet for treatment of asthma. The treatment interval was based upon reoccurrence of hives or angioedema. RESULTS: 5 of 6 patients had complete control of all symptoms and were able to eliminate most other medications within 1 week of the first dose. The 6th patient had no response. Most patients that were able to stop after 6 months have had no reoccurrences to date. CONCLUSIONS: Xolair therapy may show promise for the treatment of CIU and angioedema. The rapid control of symptoms may suggest an alternative mechanism of mast cell stabilization. Some patients may have no response to this therapy. The cost of therapy is close to that of a multiple antihistamine regiment. Controlled studies should be done in order considered to confirm our clinical findings.
Resolution of Angioedema with Omalizumab J. W. Blume, S. Kiratseavee, M. F. Sands; University at Buffalo, Buffalo, NY. RATIONALE: Omalizumab is a recombinant humanized monoclonal anti-IgE antibody FDA-approved for the treatment of moderate to severe persistent asthma. To date, there are no reports of improvement of angioedema with omalizumab. METHODS: We present a patient who experienced remission of recurrent idiopathic angioedema after omalizumab initiation. RESULTS: Our patient is a 65-year-old Caucasian male with a history of moderate persistent asthma and sarcoidosis who developed recurrent angioedema 8 years ago. He developed swelling in his feet, scrotum, face, tongue, and occasionally larynx twice weekly, requiring self-administered epinephrine, and ER visits and/or hospitalizations about twice monthly. He felt his angioedema may have been food-related, but dietary restriction of beef, peanuts, coffee, eggs, and chocolate was not beneficial. Angioedema persisted despite cessation of his ACE inhibitor and NSAIDS. Physical exam: unremarkable. Labs: CBC with differential, comprehensive metabolic panel, ANA, and TSH normal. IgE 244 (0-144 kU/L). C2 2.1 (1.64.0 mg/dL). C4 30 (16-47 mg/dL). C1 inhibitor 37 (21-39 mg/dL). C1 inhibitor function normal. C1q 16.2 (11.8-23.8 mg/dL). RAST positive to coffee (class 0/1), egg white (class 2), and beef (class 3). In November 2005, omalizumab was instituted for treatment of his asthma. Soon after omalizumab was initiatiated, the patient’s angioedema regressed. He currently remains asymptomatic. CONCLUSIONS: To our knowledge, we report the first case of control of idiopathic angioedema with omalizumab. This case suggests the need for a prospective trial of omalizumab in cases of refractory angioedema to determine possible efficacy (and mechanisms) for its utility as a therapeutic agent.
TUESDAY
Angioedema from Angiotensin I-Converting Enzyme Inhibitors May Have a Genetic Basis in AfricanAmerican Families A. Shah, D. Shats, V. Rajput; UMDNJ-Robert Wood Johnson Medical School. Cooper University Hospital, Camden, NJ. RATIONALE: Angioedema associated with angiotensin I-converting enzyme inhibitors (AE-ACEi) has a genetic predisposition. METHODS: We identify an African American female who presents with facial angioedema while on ACEi therapy. Further history reveals that her natural mother and sister had similar reactions to ACEi. We conducted a MEDLINE search of familial ACEi-associated angioedema using the keywords ‘‘angioedema,’’ ‘‘ACEi,’’ and ‘‘family history.’’ RESULTS: Twenty cases of AE-ACEi have been described within five Caucasian families with decreased aminopeptidase P (APP) activity associated with a variant in the XPNPEP2 gene. Currently there is no identification of a similar genetic variant in African-American families in the literature. Impaired bradykinin metabolism plays a central role in AEACEi. Bradykinin is degraded in the plasma by ACE and APP; however, lower plasma APP activity is reported in patients with AE-ACEi. APP activity is partially regulated by the gene XPNPEP2 in Caucasian families. CONCLUSIONS: AE-ACEi is a complex phenomenon largely modulated by genetic factors. Genes linked to APP activity appear to have a significant role in AE-ACEi and have been identified in Caucasian families. Further genetic research is needed in African-American families with AE-ACEi.