title: Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study.
abstract: BACKGROUND
  Hereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.
  
  
  METHODS
  This was a prospective, randomized, open-label, crossover study. Twenty-four subjects with mild or moderate HAE were randomly assigned during an attack-free interval to receive 1000 units of human pasteurized C1-INH concentrate IV or SC. Plasma levels of C1-INH activity and antigen, C4 antigen, cleaved high-molecular-weight kininogen (clHK), and C1-INH antibodies were measured.
  
  
  RESULTS
  The mean relative bioavailability of functional C1-INH after SC administration was 39.7%. Maximum C1-INH activity after SC administration occurred within 48 hours and persisted longer than after IV administration. C4 antigen levels increased and clHK levels decreased after IV and SC administration, indicating the pharmacodynamic action of C1-INH. The mean half-life of functional C1-INH was 62 hours after IV administration and 120 hours after SC administration (p=0.0595). C1-INH concentrate was safe and well tolerated when administered via both routes. As expected, SC administration resulted in a higher incidence of injection site reactions, all of which were mild.
  
  
  CONCLUSIONS
  With a relative bioavailability of 39.7%, SC administration of human pasteurized C1-INH yields potentially clinically relevant and sustained plasma levels of C1-INH and is safe and well tolerated.
authors.affiliation: Hemophilia Center Rhine Main GmbH, Mörfelden-Walldorf, Germany.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Martinez-Saguer
authors.forename: Marco
authors.initials: M
authors.lastname: Cicardi
authors.forename: Chiara
authors.initials: C
authors.lastname: Suffritti
authors.forename: Eva
authors.initials: E
authors.lastname: Rusicke
authors.forename: Emel
authors.initials: E
authors.lastname: Aygören-Pürsün
authors.forename: Hildegard
authors.initials: H
authors.lastname: Stoll
authors.forename: Tanja
authors.initials: T
authors.lastname: Rossmanith
authors.forename: Annette
authors.initials: A
authors.lastname: Feussner
authors.forename: Uwe
authors.initials: U
authors.lastname: Kalina
authors.forename: Wolfhart
authors.initials: W
authors.lastname: Kreuz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D054179:Angioedemas, Hereditary / Q000188:drug therapy*; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D050718:Complement C1 Inhibitor Protein