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Pharmacokinetics of Pasteurized C1-Inhibitor Concentrate (Berinert P) in 40 Patients with Hereditary Angioedema
S124 Abstracts
Temperature-dependent, Aquagenic Urticaria/anaphylaxis (tdaa) K. Shamir1, G. Browne2, V. Beltrani3, L. Bielory4; 1Allergy and Immunology, UMDNJ-New Jersey Medical School, Newark, NJ, 2Internal Medicine, UMDNJ-Robert Wood Johnson University Hospital, New Brunswick, NJ, 3Dermatology, Columbia University College of Physicians & Surgeons, New York, NY, 4Allergy, Immunology, & Rheumatology, UMDNJ-New Jersey Medical School, Newark, NJ. RATIONALE: Identifying a threshold temperature suggesting mast cell activation (development of urticaria and anaphylaxis) occurring as basal body temperature decreases following submersion in water. We describe TDAA as a linear correlation to temperature exposure, with the greater the difference between core and external aquatic temperature, the more severe the impending allergic response. METHODS: Correlating progressive torso submersions in temperature controlled water (70-93F) with severity of signs and symptoms. RESULTS: 5-year-old male with asthma presents with urticaria/anaphylaxis which occurred during swimming. 20-30 urticarial lesions developed at 82-84F water temperature following complete immersion for 40 minutes, resolving without medication within 6 hours. 5-minute exposure in a 70F pool resulted in anaphylaxis (pruritus, syncope, tachycardia, 3 urticarial lesions). Prophylactic cetirizine(2.5mg BID) provided protection to 91F (single urticarial lesion). No reaction history to showers, wading in cold water, winter play (snow angels, walks in cold wind), or drinking/holding cold beverages. Dermatographism was negative. Icecube challenge (5 minutes) produced an urticarial plaque 20 minutes post application (local reaction only). Cryofibrinogen, cryoglobulin, cold agglutinins were WNL. Further protection with periactin (4mg BID) controlled symptoms in water above 93F, allowing swimming for 1 hour. CONCLUSIONS: This is the first reported case delineating a temperature dependent systemic reaction occurring as basal body temperature decreases following submersion in water. There is a direct correlation between the body-water temperature (delta) and the reaction. Clinical signs appear as whole body temperature exposure reaches a delta of 5-7F. Further decrease in whole body-water temperature leads to progressing signs and symptoms (anaphylaxis-70F, 20-30 urticarial lesions-85F) culminating in anaphylaxis.
484
SUNDAY
Hereditary Angioedema: Safety of Long-Term Androgen Therapy C. Lee; Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA. RATIONALE: To evaluate the safety of attenuated androgens for longterm therapy of biochemically proven hereditary angioedema (HAE). METHODS: Patients were followed by one of the investigators (ALS) for up to 40 years. 47 patients had HAE confirmed by demonstration of reduced C1inhibitor and C4 serum concentrations. Clinical status was determined by questionnaire and hepatic, prostatic, lipid, and hematologic parameters were measured. RESULTS: 36 (77%) surveys were returned. Median age of respondents was 53 (range = 15 - 86) for 13 males and 23 females. 31 patients were prescribed attenuated androgens from 2 to over 30 years. Androgen administration changed in accordance with clinical demands. Of the 25 patients currently taking attenuated androgens, 15 were on stanozolol and 10 were on danazol. The current minimal maintenance dose of stanozolol was 1mg three times per week. 11 patients no longer requiring regularly scheduled therapy used medication only to control acute attacks. Reported side effects included hirsutism (10 patients), weight gain (5), menstrual irregularities (4), postmenopausal bleeding (1), acne (3), and mood changes (2). 5 patients with transient elevations of hepatic transaminases had no evidence of liver abnormalities on ultrasound. However, 2 patients without hepatic transaminitis had evidence of fatty infiltration on screening liver ultrasound. There were no persistent, serious abnormalities of liver enzymes, lipid profiles, or PSA. CONCLUSIONS: Long-term administration of attenuated androgens for HAE appears safe. Disease can be well controlled and serious abnormalities are rare when patients are evaluated every 6 months to adjust androgen dosage until any biochemical abnormalities are corrected.
485
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
Pharmacokinetics of Pasteurized C1-Inhibitor Concentrate (Berinert P) in 40 Patients with Hereditary Angioedema I. Martinez-Saguer, E. Rusicke, E. Aygören-Pürsün, W. Kreuz; Centre of Pediatrics III, Department of Hematology, Hemostaseology and Oncology, Comprehensive Care, J.-W. Goethe University Hospital Frankfurt, Germany, Frankfurt, GERMANY. RATIONALE: Hereditary deficiency of C1 inhibitor (C1-INH) function frequently results in potentially life-threatening attacks of hereditary angioedema (HAE). A pasteurized C1-INH concentrate is available to effectively treat angioedema attacks in patients with hereditary C1-INH deficiencies. Pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert® P) were evaluated in patients with HAE. METHODS: Forty patients (15 individual replacement therapy, IRT) 25 on-demand treatment) with HAE received intravenous injections of C1-INH concentrate (500-1,00U) in an attack-free interval. Blood was sampled for determination of C1-INH activity for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a singlecompartment model and IVR was determined using standard methods. RESULTS: The mean (± SD) time to maximum plasma concentration (Tmax) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the elimination half-life (t1⁄2) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours and volume of distribution at steady state (Vss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. CONCLUSIONS: C1-INH concentrate has a short Tmax and a long t1⁄2 and MRT. This is consistent with the rapid onset of clinical efficacy for C1-INH concentrate in subjects suffering from HAE attacks and the ability to effectively carry out IRT with injections administered every 2-5 days. Funding: J.-W. Goethe University Hospital Frankfurt, Germany
486
Ten Year Retrospective Study of the Contributing Factors to Angioedema in the Inpatient Allergy/Immunology Consult Service A. Banerji, P. Hesterberg, Y. Hsu, H. J. Chen, J. T. Wong; Department of Rheumatology, Allergy & Immunology, MGH, Boston, MA. RATIONALE: The causes and contributing factors of angioedema are not well described especially in inpatient settings. METHODS: A retrospective review examining causative factors of moderate to severe angioedema in patients requiring inpatient treatment and consultation by Allergy/Immunology at MGH between 1995-2004 was initated. Factors including attributing cause(s), treatment duration of causative agent(s), severity and duration of angioedema, physical examinations and laboratory findings were reviewed. In particular, we focus on potential interactions among medications in eliciting life-threatening angioedema requiring intubation. RESULTS: Sixty patients were treated for moderate to severe angioedema. Medication(s) were the most common cause of angioedema (N=59, 98%). Two or more medications were the attributing cause in the majority of cases (N=44, 75%). Patients previously stable on ACE inhibitor or Aspirin/NSAIDs appeared more likely to develop angioedema during addition of another drug (i.e., ACEI, ASA/NSAIDs, narcotics, antibiotics). ACEI and Aspirin/NSAIDs were the most common contributing medications (N=52, 88%). ACEI was the attributing cause for 33 patients (56%) and Aspirin/NSAIDs in 39 patients (66%). Twenty patients required intubation. Thirteen (65%) were attributed to ACEI and 11(55%) attributed to Aspirin/NSAIDs. ACEI + Aspirin/NSAIDs + narcotics accounted for 88% of patients needing intubation. In patients needing intubation, the combination of ACEI + Aspirin/NSAIDs (N=6, 30%) was the most frequent cause. CONCLUSIONS: Moderate to severe angioedema is often due to interacting contributions from more than one medication. The addition of another drug often led to the development of angioedema in otherwise stable patients. In particular, combinations of ACEI, ASA/NSAIDs and/or narcotics led to life-threatening angioedema requiring intubation.
487
Temperature-dependent, Aquagenic Urticaria/anaphylaxis (tdaa) K. Shamir1, G. Browne2, V. Beltrani3, L. Bielory4; 1Allergy and Immunology, UMDNJ-New Jersey Medical School, Newark, NJ, 2Internal Medicine, UMDNJ-Robert Wood Johnson University Hospital, New Brunswick, NJ, 3Dermatology, Columbia University College of Physicians & Surgeons, New York, NY, 4Allergy, Immunology, & Rheumatology, UMDNJ-New Jersey Medical School, Newark, NJ. RATIONALE: Identifying a threshold temperature suggesting mast cell activation (development of urticaria and anaphylaxis) occurring as basal body temperature decreases following submersion in water. We describe TDAA as a linear correlation to temperature exposure, with the greater the difference between core and external aquatic temperature, the more severe the impending allergic response. METHODS: Correlating progressive torso submersions in temperature controlled water (70-93F) with severity of signs and symptoms. RESULTS: 5-year-old male with asthma presents with urticaria/anaphylaxis which occurred during swimming. 20-30 urticarial lesions developed at 82-84F water temperature following complete immersion for 40 minutes, resolving without medication within 6 hours. 5-minute exposure in a 70F pool resulted in anaphylaxis (pruritus, syncope, tachycardia, 3 urticarial lesions). Prophylactic cetirizine(2.5mg BID) provided protection to 91F (single urticarial lesion). No reaction history to showers, wading in cold water, winter play (snow angels, walks in cold wind), or drinking/holding cold beverages. Dermatographism was negative. Icecube challenge (5 minutes) produced an urticarial plaque 20 minutes post application (local reaction only). Cryofibrinogen, cryoglobulin, cold agglutinins were WNL. Further protection with periactin (4mg BID) controlled symptoms in water above 93F, allowing swimming for 1 hour. CONCLUSIONS: This is the first reported case delineating a temperature dependent systemic reaction occurring as basal body temperature decreases following submersion in water. There is a direct correlation between the body-water temperature (delta) and the reaction. Clinical signs appear as whole body temperature exposure reaches a delta of 5-7F. Further decrease in whole body-water temperature leads to progressing signs and symptoms (anaphylaxis-70F, 20-30 urticarial lesions-85F) culminating in anaphylaxis.
484
SUNDAY
Hereditary Angioedema: Safety of Long-Term Androgen Therapy C. Lee; Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA. RATIONALE: To evaluate the safety of attenuated androgens for longterm therapy of biochemically proven hereditary angioedema (HAE). METHODS: Patients were followed by one of the investigators (ALS) for up to 40 years. 47 patients had HAE confirmed by demonstration of reduced C1inhibitor and C4 serum concentrations. Clinical status was determined by questionnaire and hepatic, prostatic, lipid, and hematologic parameters were measured. RESULTS: 36 (77%) surveys were returned. Median age of respondents was 53 (range = 15 - 86) for 13 males and 23 females. 31 patients were prescribed attenuated androgens from 2 to over 30 years. Androgen administration changed in accordance with clinical demands. Of the 25 patients currently taking attenuated androgens, 15 were on stanozolol and 10 were on danazol. The current minimal maintenance dose of stanozolol was 1mg three times per week. 11 patients no longer requiring regularly scheduled therapy used medication only to control acute attacks. Reported side effects included hirsutism (10 patients), weight gain (5), menstrual irregularities (4), postmenopausal bleeding (1), acne (3), and mood changes (2). 5 patients with transient elevations of hepatic transaminases had no evidence of liver abnormalities on ultrasound. However, 2 patients without hepatic transaminitis had evidence of fatty infiltration on screening liver ultrasound. There were no persistent, serious abnormalities of liver enzymes, lipid profiles, or PSA. CONCLUSIONS: Long-term administration of attenuated androgens for HAE appears safe. Disease can be well controlled and serious abnormalities are rare when patients are evaluated every 6 months to adjust androgen dosage until any biochemical abnormalities are corrected.
485
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
Pharmacokinetics of Pasteurized C1-Inhibitor Concentrate (Berinert P) in 40 Patients with Hereditary Angioedema I. Martinez-Saguer, E. Rusicke, E. Aygören-Pürsün, W. Kreuz; Centre of Pediatrics III, Department of Hematology, Hemostaseology and Oncology, Comprehensive Care, J.-W. Goethe University Hospital Frankfurt, Germany, Frankfurt, GERMANY. RATIONALE: Hereditary deficiency of C1 inhibitor (C1-INH) function frequently results in potentially life-threatening attacks of hereditary angioedema (HAE). A pasteurized C1-INH concentrate is available to effectively treat angioedema attacks in patients with hereditary C1-INH deficiencies. Pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert® P) were evaluated in patients with HAE. METHODS: Forty patients (15 individual replacement therapy, IRT) 25 on-demand treatment) with HAE received intravenous injections of C1-INH concentrate (500-1,00U) in an attack-free interval. Blood was sampled for determination of C1-INH activity for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a singlecompartment model and IVR was determined using standard methods. RESULTS: The mean (± SD) time to maximum plasma concentration (Tmax) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the elimination half-life (t1⁄2) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours and volume of distribution at steady state (Vss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. CONCLUSIONS: C1-INH concentrate has a short Tmax and a long t1⁄2 and MRT. This is consistent with the rapid onset of clinical efficacy for C1-INH concentrate in subjects suffering from HAE attacks and the ability to effectively carry out IRT with injections administered every 2-5 days. Funding: J.-W. Goethe University Hospital Frankfurt, Germany
486
Ten Year Retrospective Study of the Contributing Factors to Angioedema in the Inpatient Allergy/Immunology Consult Service A. Banerji, P. Hesterberg, Y. Hsu, H. J. Chen, J. T. Wong; Department of Rheumatology, Allergy & Immunology, MGH, Boston, MA. RATIONALE: The causes and contributing factors of angioedema are not well described especially in inpatient settings. METHODS: A retrospective review examining causative factors of moderate to severe angioedema in patients requiring inpatient treatment and consultation by Allergy/Immunology at MGH between 1995-2004 was initated. Factors including attributing cause(s), treatment duration of causative agent(s), severity and duration of angioedema, physical examinations and laboratory findings were reviewed. In particular, we focus on potential interactions among medications in eliciting life-threatening angioedema requiring intubation. RESULTS: Sixty patients were treated for moderate to severe angioedema. Medication(s) were the most common cause of angioedema (N=59, 98%). Two or more medications were the attributing cause in the majority of cases (N=44, 75%). Patients previously stable on ACE inhibitor or Aspirin/NSAIDs appeared more likely to develop angioedema during addition of another drug (i.e., ACEI, ASA/NSAIDs, narcotics, antibiotics). ACEI and Aspirin/NSAIDs were the most common contributing medications (N=52, 88%). ACEI was the attributing cause for 33 patients (56%) and Aspirin/NSAIDs in 39 patients (66%). Twenty patients required intubation. Thirteen (65%) were attributed to ACEI and 11(55%) attributed to Aspirin/NSAIDs. ACEI + Aspirin/NSAIDs + narcotics accounted for 88% of patients needing intubation. In patients needing intubation, the combination of ACEI + Aspirin/NSAIDs (N=6, 30%) was the most frequent cause. CONCLUSIONS: Moderate to severe angioedema is often due to interacting contributions from more than one medication. The addition of another drug often led to the development of angioedema in otherwise stable patients. In particular, combinations of ACEI, ASA/NSAIDs and/or narcotics led to life-threatening angioedema requiring intubation.
487