title: Modeling approach to investigate the effect of neonatal Fc receptor binding affinity and anti-therapeutic antibody on the pharmacokinetic of humanized monoclonal anti-tumor necrosis factor-α IgG antibody in cynomolgus monkey.
abstract: OBJECTIVE
  Several neonatal Fc receptor (FcRn) variants of an anti-tumor necrosis factor (TNF)-α humanized monoclonal IgG antibodies (mAbs) were developed but the effect of their differential FcRn binding affinities on pharmacokinetic (PK) behavior were difficult to be definitively measured in vivo due to formation of anti-therapeutic antibody (ATA). A semi-mechanistic model was developed to investigate the quantitative relationship between the FcRn binding affinity and PK of mAbs in cynomolgus monkey with the presence of ATA.
  
  
  METHODS
  PK and ATA data from cynomolgus monkeys which received a single intravenous dose of adalimumab, wild-type or two FcRn variant (N434H and N434A) anti-TNF-α mAbs were included in the analysis. Likelihood-based censored data handling method was used to include many PK observations with BQL values for model development. A fully integrated PK-ATA model was developed and used to fit simultaneously to the PK/ATA data.
  
  
  CONCLUSIONS
  The PK and ATA time-profiles and effect of FcRn-binding affinity on PK of mAbs were well described by the model and the parameters were estimated with good precision. The model was used successfully to construct quantitative relationships between FcRn binding affinity and PK of anti-TNF-α mAbs in the presence of the ATA-mediated elimination and interferences.
authors.affiliation: Clinical Pharmacology and Therapeutic, Children Hospital of Philadelphia, PA, United States; School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: ngc1@email.chop.edu.
authors.forename: Chee M
authors.initials: CM
authors.lastname: Ng
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Loyet
authors.forename: Suhasini
authors.initials: S
authors.lastname: Iyer
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008252:Macaca fascicularis; D011485:Protein Binding / Q000276:immunology*; D011961:Receptors, Fc / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha; C100688:Fc receptor, neonatal
keywords: Anti-therapeutic antibody; FcRn; Immunogenicity; Pharmacokinetic and pharmacodynamic modeling; Therapeutic monoclonal IgG antibody; Tumor necrosis factor-alpha