Peter Kiessling

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.

BACKGROUND Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. OBJECTIVE To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. METHODS This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. RESULTS Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. CONCLUSION C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home

The lifelong IgG replacement therapy for patients with primary immunedeficiencies (PIDD) may be provided by intravenous (IVIG) or by subcutaneous IgG (SCIG) infusions. We investigated the impact of weekly SCIG self-infusions at home on the health-related quality of life, treatment satisfaction, and preferences in patients treated with IVIG at the hospital/doctors office (Group A) or at home (Group B) before the study started. Forty-four adult North American PIDD patients were included in the study, 28 patients in Group A and 16 in Group B. Patients in Group A reported significantly less limitations with their work/daily activities, a significantly improved vitality, and better general health. Treatment satisfaction was significantly improved in Group A. The preference for the subcutaneous route and for home therapy was respectively 81% and 90% in Group A. In Group B, 69% preferred the subcutaneous route and 92% home therapy.

Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies

Bioavailability and pharmacokinetics of subcutaneous IgG (SCIG) and intravenous IgG (IVIG) differ. It is not clear if and/or how the dose should be adjusted when switching from IVIG to SCIG. Area under the curve (AUC) of serum IgG versus time and trough level ratios (TLRs) on SCIG/IVIG were evaluated as guides for adjusting the dose. The mean dose adjustments required for non-inferior AUCs with 2 different SCIG preparations were 137% (± 12%) and 153% (± 16%). However, there were wide variations between adjustments required by different subjects, and in the resulting TLRs. In contrast, combined data from multiple studies allow estimation of the ratio of IgG levels with different dose adjustments, and of the steady state serum levels with different SCIG doses. When switching a patient from IVIG to SCIG, individualizing the dosage based on measured serum IgG levels and the clinical response is preferable to using mean pharmacokinetic parameters.

Phase I comparability of recombinant human albumin and human serum albumin

Recombinant human albumin (rHA) is a highly purified animal‐, virus‐, and prion‐free product developed as an alternative to human serum albumin (HSA), to which it is structurally equivalent. The present investigation compared the safety, tolerability, and pharmacokinetics/pharmacodynamics of rHA with HSA. Two double‐blind, randomized trials were performed in healthy volunteers using intramuscular (IM) and intravenous (IV) administration. The IM trial included 500 volunteers, each receiving 5 repeat doses of 5 mg (100 subjects), 15 mg (100 subjects), or 65 mg (300 subjects) of rHA or HSA. Thirty volunteers participated in the IV trial, each receiving ascending doses (10 g, 20 g, and 50 g) of either rHA or HSA. In both trials, all adverse events were recorded and conventionally classified; potential allergic responses were also monitored. Blood samples were taken in both studies to test for IgG or IgE antibodies against test products and potential impurities. For the IV study, pharmacokinetic/pharmacodynamic assessments were performed, including measurement of serum albumin, colloid osmotic pressure, and hematocrit pre‐ and postinfusion. Nine subjects in the IM study (4 recipients of rHA and 5 of HSA) reported drug‐related, potentially allergic events; all but 2 of these were skin related. No serious or potentially allergic events were reported with either product in the IV study. There was no immunological response to either product, and dose level did not influence the study outcomes. Serum albumin, colloid osmotic pressure changes, and hematocrit ratio were as expected, with no differences between rHA and HSA. rHA and HSA exhibited similar safety, tolerability, and pharmacokinetic/pharmacodynamic profiles, with no evidence of any immunological response.

Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks

BACKGROUND C1 esterase inhibitor (C1-INH) replacement is recommended as a first-line therapy for acute edema attacks in hereditary angioedema (HAE). Only limited pharmacokinetic analyses of the administered C1-INH in plasma are available. OBJECTIVE To investigate retrospectively the population pharmacokinetics of a plasma-derived C1-INH (pC1-INH) concentrate used to treat acute HAE attacks in a randomized, placebo-controlled phase 2/3 study in patients with HAE. METHODS Acute abdominal and facial attacks were treated with either a pC1-INH concentrate (Berinert) at single intravenous doses of 10 or 20 U/kg body weight or placebo. Plasma sampling was conducted 0, 1, and 4 hours after dosing. A nonlinear retrospective population pharmacokinetic model was obtained using the assumption of a 1-compartment model. RESULTS The final population pharmacokinetic model was based on data from 97 patients treated with 10 or 20 U/kg of pC1-INH concentrate. The estimated mean half-life was 32.7 hours (90% confidence interval, 16.6-48.8 hours), and the estimated mean clearance was 0.92 mL/kg/h (90% confidence interval, 0.50-1.33 mL/kg/h). CONCLUSIONS The half-life of the same pC1-INH concentrate reported in a previous study was confirmed by this retrospective population pharmacokinetic analysis in patients treated for acute HAE attacks. In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided.

Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angioedema attacks

BACKGROUND hereditary angioedema (HAE) is a rare disorder characterized by a quantitative or functional deficiency of C1 esterase inhibitor (C1-INH), resulting in periodic attacks of acute edema at various body locations. The symptoms of these painful attacks can be treated effectively with C1-INH concentrate. OBJECTIVE to document the efficacy and safety of a weight-based dose of C1-INH concentrate in the treatment of successive HAE attacks at abdominal and facial locations. METHODS acute facial and abdominal attacks were each treated with C1-INH concentrate using a single intravenous dose of 20 U/kg body weight. Efficacy end points included patient-reported time to onset of symptom relief and time to complete resolution of all symptoms. Safety was assessed by monitoring adverse events and assaying for markers of viral infection. RESULTS we treated 663 abdominal attacks in 50 patients and 43 facial attacks in 16 patients (a total of 706 attacks in 53 patients). The median time to onset of relief for all attacks was 19.8 minutes, with a median time to complete resolution of 11.0 hours. The median time to onset of relief was 19.8 minutes for abdominal attacks and 28.2 minutes for facial attacks, indicating efficacy for both types of attack. No treatment-related serious adverse events occurred, and C1-INH concentrate was well tolerated. No human immunodeficiency virus, hepatitis virus, or parvovirus B19 infections arose during the study. CONCLUSION the C1-INH concentrate dose of 20 U/kg provides rapid, effective, and safe treatment for successive HAE attacks at abdominal and facial locations.

Hereditary angioedema: Validation of the end point time to onset of relief by correlation with symptom intensity.

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.