title: Pharmacokinetic and pharmacodynamic relationship of AMG 811, an anti-IFN-γ IgG1 monoclonal antibody, in patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  To investigate the relationships between AMG 811 exposure, concentration changes in serum IFN-γ, and IFN-γ-induced protein 10 (CXCL10), and to identify important contributions of baseline covariates to these relationships.
  
  
  METHODS
  A mechanism based pharmacokinetic (PK)-pharmacodynamic (PD) model was developed. A target mediated disposition model was used to describe AMG 811 and target IFN-γ interaction. CXCL10 was predicted to be driven by estimated free IFN-γ levels.
  
  
  RESULTS
  For an average systemic lupus erythematosus (SLE) subject, the linear clearance (CL) of AMG 811 was 0.176 L/day, and the central (Vc) and peripheral (Vp) volumes of distribution were 1.48 and 2.12 L, respectively. Body weight was found to correlate with CL, Vc, Vp, and inter compartment clearance (Q); and age was found to correlate with Vc. The relationship between estimated free serum IFN-γ concentration levels and serum CXCL10 in logarithmic scales was best described by a linear model with slope and intercept estimated to be 0.197 and -0.3, respectively.
  
  
  CONCLUSIONS
  The largest observed reduction of serum CXCL10 concentration was achieved at the highest AMG 811 dose tested (180 mg SC). This model enables simulations of AMG 811 PK-PD profiles under various dosing regimens to support future clinical studies.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Thousand Oaks, California, USA, pingc@amgen.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Thuy
authors.initials: T
authors.lastname: Vu
authors.forename: Adimoolam
authors.initials: A
authors.lastname: Narayanan
authors.forename: Winnie
authors.initials: W
authors.lastname: Sohn
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Boedigheimer
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Welcher
authors.forename: Barbara
authors.initials: B
authors.lastname: Sullivan
authors.forename: David A
authors.initials: DA
authors.lastname: Martin
authors.forename: Juan Jose Perez
authors.initials: JJ
authors.lastname: Ruixo
authors.forename: Peiming
authors.initials: P
authors.lastname: Ma
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D016014:Linear Models; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: C000604956:AMG 811; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007371:Interferon-gamma