title: FG-3019, a Human Monoclonal Antibody Recognizing Connective Tissue Growth Factor, is Subject to Target-Mediated Drug Disposition.
abstract: To evaluate and model the pharmacokinetic and pharmacodynamic behavior in rats of FG-3019, a human monoclonal antibody targeting connective tissue growth factor (CTGF).
  
  
  
  FG-3019, human CTGF (rhCTGF), or the N-terminal domain of rhCTGF were administered intravenously to rats and concentrations of these proteins as well as endogenous CTGF were determined by immunoassays. FG-3019, or (125)I-labeled FG-3019, and human CTGF (rhCTGF) were co-administered to assess the impact of CTGF on the elimination rate and tissue localization of FG-3019, which was further characterized by immunohistochemical analysis. A PK/PD model for target-mediated elimination of FG-3019 was developed to fit the kinetic data.
  
  
  
  FG-3019 exhibited non-linear pharmacokinetics in rats. Circulating concentrations of the N-terminal half of CTGF increased after dosing with FG-3019, reached maximal levels after 1-5 days, and returned toward baseline levels as FG-3019 cleared from the circulation, whereas the concentration of intact CTGF was unaffected by administration of FG-3019. Co-administration of rhCTGF dramatically enhanced the rate of FG-3019 elimination, redistributing the majority of (125)I-labeled FG-3019 from the blood to the liver, kidney, spleen and adrenal gland. FG-3019 co-administered with CTGF was found along the sinusoids of the liver and adrenal glands, the capillaries of the kidney glomeruli and in the spleen. A pharmacokinetic model for target-mediated elimination of FG-3019 was used to fit the time courses of FG-3019 and endogenous CTGF plasma concentrations, as well as time courses of rhCTGF and rhCTGF N-fragment after intravenous administration of these species.
  
  
  
  FG-3019 is subject to target mediated elimination in rats.
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA. mbrenner@fibrogen.com.
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Brenner
authors.affiliation: Department of Pharmaceutical Sciences, State University of New York at Buffalo, 370 Kapoor Hall, Buffalo, New York, 14214, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: James Z
authors.initials: JZ
authors.lastname: Chou
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Pierre E
authors.initials: PE
authors.lastname: Signore
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Cyra K
authors.initials: CK
authors.lastname: Fung
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: David
authors.initials: D
authors.lastname: Guzman
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Li
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Olsen
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Viet-Tam L
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Carolyn W
authors.initials: CW
authors.lastname: Koo
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Sternlicht
authors.affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, California, 94158, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D055513:Connective Tissue Growth Factor / Q000008:administration & dosage* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C526317:CCN2 protein, human; D011994:Recombinant Proteins; D055513:Connective Tissue Growth Factor; C560078:pamrevlumab
keywords: CTGF; Connective Tissue Growth Factor; FG-3019; TMDD