Catabolism of C1 inhibitor influences the response to replacement therapy in hereditary angioedema
Authors: Marco Cicardi, Andrea Zanichelli, Chiara Suffritti, Maddalena A. Wu, Thomas Machnig, Annalisa De Silvestri, Mario Regazzi, Carmine Tinelli
Journal: Journal of Allergy and Clinical Immunology (2016)

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling attacks mediated by bradykinin, which is released on activation of the contact system in patients lacking the C1 inhibitor (C1-INH).1Cicardi M. Aberer W. Banerji A. Bas M. Bernstein J.A. Bork K. et al.Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.Allergy. 2014; 69: 602-616Crossref PubMed Scopus (482) Google Scholar Replacement therapy with intravenous plasma-derived C1-INH (pdC1-INH) aims at restoring control of bradykinin release by maintaining protective C1-INH activity trough levels.2Späth P.J. Wüthrich B. Bütler R. Quantification of C1-inhibitor functional activities by immunodiffusion assay in plasma of patients with hereditary angioedema–evidence of a functionally critical level of C1-inhibitor concentration.Complement. 1984; 1: 147-159Crossref PubMed Scopus (60) Google Scholar Approved doses of pdC1-INH, 1000 IU twice weekly for prophylaxis,3Zuraw B.L. Kalfus I. Safety and efficacy of prophylactic nanofiltered C1-inhibitor in hereditary angioedema.Am J Med. 2012; 125: 938.e1-938.e7Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are generally effective but can fail in some patients with severe C1-INH-HAE.4Bouillet L. Boccon-Gibod I. Dumestre-Perard C. Cesbron J.Y. Massot C. Efficacy of icatibant treatment in patients with hereditary angio-oedema type I resistant to treatment with C1 inhibitor concentrate.Br J Dermatol. 2011; 164: 1406-1407Crossref PubMed Scopus (6) Google Scholar This prospective, single-center, open-label study was designed to assess whether catabolism of C1-INH influences the response to pdC1-INH therapy in poor-response patients with severe C1-INH-HAE. Pharmacokinetic (PK) and pharmacodynamic (PD) parameters were evaluated before and after repetitive administration of high pdC1-INH doses (Berinert, CSL Behring, Marburg, Germany). During the loading period, daily 3000 IU pdC1-INH infusions were repeated until 24-hour postinfusion functional C1-INH levels exceeded 70% of normal. In the maintenance period, 3000 IU was administered 3 times weekly for 5 weeks, followed by 2000 IU twice weekly for 3 weeks. Adverse events, vital signs, and concomitant medications were monitored, revealing no safety findings of note. One poor-response patient was enrolled; a 75-year-old woman with C1-INH-HAE due to a c.1475T>A (p.Met492Lys) mutation. She experienced up to 100 attacks annually. On-demand pdC1-INH and icatibant provided only limited benefit; prophylaxis with pdC1-INH, tranexamic acid, and danazol remained ineffective. At the time of the study, she received on-demand pdC1-INH or icatibant up to twice weekly. Seventeen patients with C1-INH-HAE with normal responses to pdC1-INH served as retrospective controls, providing blood samples obtained before and after 20 attacks that were treated with pdC1-INH (Berinert, CSL Behring). Laboratory measurements were performed as previously described.5Suffritti C. Zanichelli A. Maggioni L. Bonanni E. Cugno M. Cicardi M. High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency.Clin Exp Allergy. 2014; 44: 1503-1514Crossref PubMed Scopus (68) Google Scholar, 6Cicardi M. Beretta A. Colombo M. Gioffré D. Cugno M. Agostoni A. Relevance of lymphoproliferative disorders and of anti-C1 inhibitor autoantibodies in acquired angio-oedema.Clin Exp Immunol. 1996; 106: 475-480Crossref PubMed Scopus (91) Google Scholar Functional and antigenic C1-INH concentrations were best fitted by 1-compartment models. P-Pharm population PK modeling software was used (version 3, Simed). For the poor-response patient, the elimination half-life was derived from estimated PK parameters (T1/2 = 0.693 × apparent volume of distribution[VD]/apparent total plasma clearance [CL]). The area under the concentration-time curve during a dosing interval τ (AUCτ) was estimated by the trapezoidal rule. The average plasma concentration at steady-state (Css) during τ was calculated as AUCτ/τ. Statistical analyses were performed using STATA software (version 13; StataCorp LLC, College Station, Tex). Quantitative data were summarized as mean, SD, and coefficient of variation. Relationships between quantitative variables were analyzed with the Pearson correlation coefficient (r). Comparisons between patients were made using a 1-sample t test. The study was conducted in accordance with the Declaration of Helsinki and approved by the local Independent Ethics Committee (Ospedale Luigi Sacco, Milan, Italy). Written informed consent was obtained from the poor-response patient. The control patients had given written consent for their samples to be used for research purposes. The poor-response patient had preinfusion levels of functional C1-INH, C4, and C1q below detection limits, 25% of normal for antigenic C1-INH, and 60% for cleaved high-molecular-weight kininogen (HK). After 3 days with 3000 IU pdC1-INH, the maintenance period could start. During 5 weeks with 3000 IU 3 times weekly, mean preinfusion functional and antigenic C1-INH levels were 46% and 57% of normal, respectively, increasing to 86% and 53% postinfusion (Table I). C4 and C1q and cleaved HK reached the normal ranges on days 4 and 2 and remained there (Fig 1). The patient took additional on-demand icatibant once.Table IFunctional and antigenic C1-INH concentrations in the poor-response patient during the maintenance periodConcentrationMean concentration in % (SD; CV)PreinfusionPostinfusion, 10 min after end of infusionFunctional C1-INH 9000 IU/wk (3000 IU, 3 times weekly)46 (30; 66)86 (27; 31) 4000 IU/wk (2000 IU, twice weekly)18 (10; 59)53 (10; 20)Antigenic C1-INH 9000 IU/wk (3000 IU, 3 times weekly)57 (23; 40)112 (23; 21) 4000 IU/wk (2000 IU, twice weekly)30 (12; 42)71 (15; 22)CV, Coefficient of variation. Open table in a new tab CV, Coefficient of variation. During 3 weeks with 2000 IU twice weekly, mean preinfusion functional and antigenic C1-INH levels were 18% and 30% of normal, increased to 53% and 71% postinfusion (Table I), but decreased rapidly thereafter (see Fig E1 in this article's Online Repository at www.jacionline.org). C1q remained within the normal range, C4 decreased to below 60% of normal, and HK remained above 40% (Fig 1). The patient experienced 5 attacks treated with icatibant and 1 without additional treatment. Functional and antigenic C1-INH levels estimated for the poor-response patient from population PK models correlated well with the observed levels (r = 0.85, P < .001 and r = 0.87, P < .001, respectively). At steady-state, 9000 IU pdC1-INH weekly was estimated to result in average weekly systemic exposures (AUC) of functional and antigenic C1-INH of 11,487 h.% (dose/CL) and 12,941 h.%, respectively, and average Css of 68.4% (AUC/168 h) and 77.1% (Fig E1). A dose of 4000 IU weekly was estimated to result in average AUC of 5833 h.% and 7329 h.% and average Css of 34.6% and 43.1%. CL of antigenic C1-INH was estimated at 0.51 IU/(h.%), Vd at 25.4 IU/%, and T1/2 at 34.3 hours. Estimated CL of functional C1-INH was significantly lower for the control patients than for the poor-response patient (0.37 vs 0.56 IU/[h.%]; P = .002); Vd showed no significant difference (35.0 vs 27.3 IU/%; P = .19). Plasma recovery of C1-INH after infusion of pdC1-INH was lower and clearance faster in our poor-response patient than in normal responders. She had no evidence of autoimmune or other disease and normal transaminase plasma levels. Concurrently with the worsening of symptoms, she had depletion of C4 and C1q and massive HK cleavage, indicating a profound degree of instability in the complement and contact systems. With high doses of pdC1-INH, PD parameters normalized and symptoms disappeared, recurring upon dose reduction. At either dose, PK parameters were consistent, with similar percentages of protein cleared from plasma. In some patients with acquired C1-INH deficiency, symptoms are induced by autoantibodies that consume C1-INH.7Malbran A. Hammer C.H. Frank M.M. Fries L.F. Acquired angioedema: observations on the mechanism of action of autoantibodies directed against C1 esterase inhibitor.J Allergy Clin Immunol. 1988; 81: 1199-1204Abstract Full Text PDF PubMed Scopus (47) Google Scholar In our poor-response patient, however, no C1-INH antibodies were detected. Other physiologic pathways of C1-INH catabolism include interaction with target proteases or binding to hepatic asialoglycoprotein receptors.8Minta J.O. The role of sialic acid in the functional activity and the hepatic clearance of C1-INH.J Immunol. 1981; 126: 245-249PubMed Google Scholar In our poor-response patient, high doses of pdC1-INH apparently normalized PD parameters and controlled clinical symptoms without changing the PK, suggesting that clearance of C1-INH was not dependent on the catabolic pathways provided by protease-inhibitor interaction. Therefore, changes in the expression of hepatic asialoglycoprotein receptors, related to still undefined circumstances, could explain increased C1-INH clearance in our poor-response patient. Cirrhosis, often accompanied by increased expression of asialoglycoprotein receptors,9Witzigmann D. Quagliata L. Schenk S.H. Quintavalle C. Terracciano L.M. Huwyler J. Variable asialoglycoprotein-receptor 1 expression in liver disease: implications for therapeutic intervention.Hepatol Res. 2016; 46: 686-696Crossref PubMed Scopus (44) Google Scholar was excluded. We conclude that differences in treatment response to pdC1-INH replacement therapy may be connected to differences in hepatic clearance of the infused C1-INH protein rather than hyperactivation of the complement and contact systems in patients with highly symptomatic C1-INH-HAE. We thank Christina Eichhorn, Eva Kestner, and Douglas Fiebig (Trilogy Writing & Consulting GmbH) for medical writing services on behalf of CSL Behring GmbH.