title: Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.
abstract: BACKGROUND
  Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.
  
  
  OBJECTIVE
  To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B.
  
  
  METHODS
  In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24).
  
  
  RESULTS
  Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose.
  
  
  CONCLUSIONS
  Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.
authors: Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London, UK.
authors: P
authors: P
authors: Chowdary
authors: S
authors: S
authors: Lethagen
authors: U
authors: U
authors: Friedrich
authors: B
authors: B
authors: Brand
authors: C
authors: C
authors: Hay
authors: F
authors: F
authors: Abdul Karim
authors: R
authors: R
authors: Klamroth
authors: P
authors: P
authors: Knoebl
authors: M
authors: M
authors: Laffan
authors: J
authors: J
authors: Mahlangu
authors: W
authors: W
authors: Miesbach
authors: J
authors: J
authors: Dalsgaard Nielsen
authors: M
authors: M
authors: Martín-Salces
authors: P
authors: P
authors: Angchaisuksiri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006467:Hemophilia A / Q000188:drug therapy*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D010919:Placebos; C574488:concizumab
keywords: hemophilia; mAb 2021; pharmacokinetics; safety; tissue factor pathway inhibitor