title: Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen®.
abstract: BACKGROUND
  Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34+) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics.
  
  
  METHODS
  Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence.
  
  
  RESULTS
  The results reported in this work demonstrate that BK0023 is comparable in terms of biological activity, efficacy and safety to Neupogen®.
  
  
  CONCLUSIONS
  BK0023 has the same pharmacokinetic profile, efficacy and safety as the reference commercial filgrastim Neupogen® and therefore could be further developed to become a convenient option to treat neutropenia in oncological patients.
authors.affiliation: Bio-Ker S,r,l,-Multimedica Group, Sardinia Scientific and Technological Park, Building 3, I-09010 Pula Cagliari, Italy. davide.crobu@multimedica.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Crobu
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Schrepfer
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Tonon
authors.forename: Gloria Saccani
authors.initials: GS
authors.lastname: Jotti
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Onali
authors.forename: Simona
authors.initials: S
authors.lastname: Dedoni
authors.forename: Gaetano
authors.initials: G
authors.lastname: Orsini
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Stefano
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D018592:Cross-Over Studies; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D009503:Neutropenia / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013810:Therapeutic Equivalency; D016896:Treatment Outcome
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim