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

Hereditary angioedema (HAE), caused by functional deficiency of C1-esterase inhibitor1 (C1-INH), is a rare disease characterized by recurrent, spontaneous, nonallergic edema in subcutaneous (SC) tissues and mucous membranes. In case of laryngeal edema, HAE is associated with high mortality rates when there is a delay in treating the attacks.2,3 HAE is a debilitating disease that can have a severe effect on quality of life. C1-INH is a serine protease inhibitor that controls vascular permeability by acting on the initial activation phase of the complement, coagulation, contact, and fibrinolytic systems. The functional deficiency of C1-INH leads to increased activation of plasma kallikrein and Factor (F)XIIa with a subsequent release of bradykinin, which is a key mediator of vascular permeability.4 Additionally, C1-INH is the main inhibitor of FXIa, which plays an important role in the generation of thrombin, a positive modulator of vasopermeability.5-8 HAE Type I results from a quantitative deficiency in functional C1-INH, whereas the less common HAE Type II, affecting 15% of patients, results from a dysfunctional form of C1-INH circulating at normal or elevated plasma concentrations.4 Both defects are inherited as an autosomal dominant trait. HAE Type III is extremely rare, with mainly women being clinically affected; it is not associated with C1-INH deficiency and its pathophysiology is uncertain.9 Common anti-inflammatory treatments, such as corticosteroids, antihistamines, or epinephrine, are usually inappropriate for treating acute attacks caused by HAE.10 Clinical studies,11-13 as well as more than 30 years of clinical use,14,15 have shown that intravenous (IV) C1-INH replacement therapy with human C1-INH concentrate is an effective and safe treatment for acute edema attacks in patients with HAE. Therefore, C1-INH concentrate is recommended as first-line therapy in this indication.16 In patients with HAE requiring frequent IV treatment with C1-INH concentrate, either for acute edema attacks or for prophylaxis, venous access may become difficult over time. The SC administration of C1-INH concentrate is therefore being investigated as a potential alternative therapeutic approach, specifically for the prophylactic treatment of HAE. In support of this approach, a preclinical study with CSL Behring's human pasteurized C1-INH concentrate (Berinert, CSL Behring, Marburg, Germany) revealed a relative bioavailability of approximately 70% after SC administration in rabbits, compared with IV administration (Ingo Pragst, CSL Behring, May 2013). Building on this preclinical experience, the primary objective of our study was to compare the pharmacokinetics of the same preparation of C1-INH concentrate after IV and SC administration in subjects with mild or moderate HAE during an attack-free interval, evaluating the relative bioavailability of SC administration based on plasma levels of C1-INH activity. In addition to assessing the safety and tolerability of C1-INH concentrate when administered via both these routes, we also assessed plasma levels of C1-INH antigen and cleaved high-molecular-weight kininogen (clHK), serum levels of C4 antigen, and the presence of C1-INH antibodies after treatment. These additional endpoints were assessed to provide insight into the pharmacokinetic and pharmacodynamic effects of the C1-INH concentrate administered.