title: Nonclinical Evaluation of PF-06438179: A Potential Biosimilar to Remicade®(Infliximab).
abstract: PF-06438179, a potential biosimilar to Remicade®(infliximab, Janssen Biotech, Inc.), is a chimeric mouse-human monoclonal antibody targeting human tumor necrosis factor alpha (TNF).
  
  
  
  Analytical (small subset reported here) and nonclinical studies compared the structural, functional, and in vivo nonclinical similarity of PF-06438179 with Remicade sourced from the United States (infliximab-US) and/or European Union (infliximab-EU).
  
  
  
  The peptide map profiles were superimposable, and peptide masses were the same, indicating identical amino acid sequences. Data on post-translational modifications, biochemical properties, and biological function provided strong support for analytical similarity. Administration of a single intravenous (IV) dose (10 or 50 mg/kg) of PF-06438179 or infliximab-EU to male rats was well tolerated. There were no test article-related clinical signs or effects on body weight or food consumption. Systemic exposures [maximum drug concentration (Cmax) and area under the concentration-time curve (AUC)] in rats administered PF-06438179 or infliximab-EU were similar, with mean exposure ratio of PF-06438179 relative to infliximab-EU ranging from 0.88 to 1.16. No rats developed anti-drug antibodies. A 2-week IV toxicity study was conducted with once-weekly administration of 10 or 50 mg/kg of PF-06438179 to male and female rats. PF-06438179-related hyperplasia of sinusoidal cells occurred in the liver in rats administered 50 mg/kg, but was not adverse based on its minimal to mild severity. The no-observed adverse-effect level for PF-06438179 was 50 mg/kg. At this dose, Cmaxwas 1360 µg/mL and AUC at 168 h was 115,000 µg h/mL on day 8.
  
  
  
  The analytical and nonclinical studies have supported advancement of PF-06438179 into global comparative clinical trials.
  
  
  
  Pfizer Inc.
authors: Pfizer Inc., Drug Safety Research and Development, Andover, MA, USA. mazin.derzi@pfizer.com.
authors: Mazin
authors: M
authors: Derzi
authors: Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, San Diego, CA, USA.
authors: Theodore R
authors: TR
authors: Johnson
authors: Pfizer Inc., Drug Safety Research and Development, Groton, CT, USA.
authors: Ahmed M
authors: AM
authors: Shoieb
authors: Pfizer Inc., Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Andover, MA, USA.
authors: Hugh D
authors: HD
authors: Conlon
authors: Pfizer Inc., Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Andover, MA, USA.
authors: Penny
authors: P
authors: Sharpe
authors: Pfizer Inc., Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Andover, MA, USA.
authors: Andrew
authors: A
authors: Saati
authors: Pfizer Inc., Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Andover, MA, USA.
authors: Sarah
authors: S
authors: Koob
authors: Pfizer Inc., Drug Safety Research and Development, Andover, MA, USA.
authors: Michael W
authors: MW
authors: Bolt
authors: Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, Groton, CT, USA.
authors: Leslie G
authors: LG
authors: Lorello
authors: Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, Andover, MA, USA.
authors: Jim
authors: J
authors: McNally
authors: Pfizer Inc., Global Technology Services, Biomanufacturing Sciences, St. Louis, MO, USA.
authors: Carol F
authors: CF
authors: Kirchhoff
authors: Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, Groton, CT, USA.
authors: Teresa A
authors: TA
authors: Smolarek
authors: Pfizer Inc., Drug Safety Research and Development, Andover, MA, USA.
authors: Michael W
authors: MW
authors: Leach
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D059451:Biosimilar Pharmaceuticals / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000069285:Infliximab / Q000494:pharmacology*; D008297:Male; D051381:Rats; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab
keywords: Biosimilar; Infliximab; Liver; Monoclonal antibody; Remicade; Rheumatology; Toxicity; Toxicokinetics; Tumor necrosis factor