title: Pharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in Cynomolgus monkeys after iv and sc administration.
abstract: BACKGROUND
  Concizumab (mAb 2021) is a monoclonal IgG4 antibody (mAb) that binds to the Kunitz-type protease inhibitor (KPI) 2 domain of TFPI thereby blocking the interaction of this domain with the active site of FXa. The objective of the present study was to characterize the pharmacokinetics of concizumab in Cynomolgus monkeys after intravenous (iv) and subcutaneous (sc) administration.
  
  
  METHODS
  Data from two studies were included in the modelling, all in all data from 52 monkeys distributed into 9 groups. Three groups received three escalating sc doses of concizumab with a one week dosing interval, two groups were administered a single dose, and four groups received multiple doses over 13 weeks of concizumab. The plasma concentration was measured using a standard ELISA, and pharmacokinetic data were analysed using NONMEM.
  
  
  RESULTS
  The pharmacokinetics of concizumab were characterised by a high bioavailability (93%) after sc administration. The time course of the elimination of concizumab from the circulation was well described by the proposed target mediated drug disposition (TMDD) model. The clearance of concizumab was estimated to be 0.14 ml/h/kg, the target clearance was characterized by a 50% saturation level of 0.54 μg/ml (Km), and the clearance at target saturation was estimated to be 11 μg/h/kg.
  
  
  CONCLUSIONS
  Concizumab displays a typical TMDD profile with important implications for a putative treatment regime in haemophilia patients. Compared to current standard haemophilia treatment, concizumab has a high bioavailability after sc administration and may provide a viable alternative to intravenous dosing for the treatment of haemophilia.
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark. Electronic address: hkag@novonordisk.com.
authors.forename: Henrik
authors.initials: H
authors.lastname: Agersø
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Rune Viig
authors.initials: RV
authors.lastname: Overgaard
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Mads Bjelke
authors.initials: MB
authors.lastname: Petersen
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Mette Brunsgaard
authors.initials: MB
authors.lastname: Hermit
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Mette Høgh
authors.initials: MH
authors.lastname: Sørensen
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Petersen
authors.affiliation: Research and Development, Novo Nordisk A/S, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Hilden
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D020134:Catalytic Domain; D015951:Factor Xa / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism*; D008252:Macaca fascicularis; D008954:Models, Biological
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; C574488:concizumab; D015951:Factor Xa
keywords: Concizumab; Haemophilia; Nonmem; TFPI; TMDD; mAb 2021