title: Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti-TNF-like weak inducer of apoptosis (anti-TWEAK) monoclonal antibody.
abstract: Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is implicated in the pathogenesis of lupus nephritis. This study evaluated the pharmacokinetics, using the population approach, and pharmacodynamics of BIIB023, an anti-TWEAK monoclonal antibody, in healthy Chinese, Japanese and Caucasian volunteers.
  
  
  
  In this single-dose, randomized, double-blind, phase 1 study of BIIB023 in healthy volunteers, BIIB023 was administered by intravenous infusion (3 or 20 mg kg(-1) ) on Day 1; follow-up occurred through Day 71. BIIB023 serum concentration was measured using a validated enzyme-linked immunosorbent assay; BIIB023 concentration-time data were subjected to noncompartmental analysis. Population pharmacokinetic analysis was performed using data from this study and a prior phase 1 study of BIIB023 in subjects with rheumatoid arthritis. Soluble TWEAK and
  
  
  
  BIIB023 complex were evaluated.
  
  
  
  There were no differences in BIIB023 pharmacokinetics requiring dose adjustment among the three ethnic groups or between healthy volunteers and arthritis patients. BIIB023 central compartment volume (3050 ml) and clearance (7.42 ml h(-1) ) were comparable to those observed for other monoclonal antibody drugs. BIIB023 serum exposure increased in a dose-dependent manner in all groups, but not in direct proportion to dose level; at concentrations below ~10 μg ml(-1) , nonlinear clearance was observed. Soluble TWEAK levels decreased to below the level of quantitation after BIIB023 treatment, with concomitant changes in
  
  
  
  BIIB023 complex levels.
  
  
  
  No clinically meaningful differences were observed in BIIB023 pharmacokinetic and pharmacodynamic properties in healthy Chinese, Japanese and Caucasian volunteers; pharmacodynamic measures suggested target engagement. TWEAK may be an attractive therapeutic target for lupus nephritis treatment.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Galluppi
authors.affiliation: Clinical Development Immunology, Biogen, Berkshire, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wisniacki
authors.affiliation: Translational Sciences, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Stebbins
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D044466:Asian People; D000080908:Broadly Neutralizing Antibodies; D000074049:Cytokine TWEAK / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D017711:Nonlinear Dynamics; D044465:White People; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C586995:BIIB023; D000080908:Broadly Neutralizing Antibodies; D000074049:Cytokine TWEAK; C109743:TNFSF12 protein, human
keywords: BIIB023; TWEAK protein; human; pharmacodynamics; pharmacokinetics