title: Use of population approach non-linear mixed effects models in the evaluation of biosimilarity of monoclonal antibodies.
abstract: OBJECTIVE
  Population pharmacokinetic analyses (PPK) have been used to establish bioequivalence for small molecules and some biologicals. We investigated whether PPK could also be useful in biosimilarity testing for monoclonal antibodies (MAbs).
  
  
  METHODS
  Data from a biosimilarity trial with two trastuzumab products were used to build population pharmacokinetic models. First, a combined model was developed and similarity between test and reference product was evaluated by performing a covariate analysis with trastuzumab drug product (test or reference) on all model parameters. Next, two separate models were developed, one for each drug product. The model structure and parameters were compared and evaluated for differences.
  
  
  RESULTS
  Drug product could not be identified as statistically significant covariate on any parameter in the combined model, and the addition of drug product as covariate did not improve the model fit. A similar structural model described both the test and reference data best. Only minor differences were found between the estimated parameters from these separate models.
  
  
  CONCLUSIONS
  PPK can also be used to support a biosimilarity claim for a MAb. However, in contrast to the standard non-compartmental analysis, there is less experience with a PPK approach. Here, we describe two methods of how PPK can be incorporated in biosimilarity testing for complex therapeutics.
authors: Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands. info@chdr.nl.
authors: Joannes A A
authors: JA
authors: Reijers
authors: Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands.
authors: T
authors: T
authors: van Donge
authors: Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands.
authors: F M L
authors: FM
authors: Schepers
authors: Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands.
authors: J
authors: J
authors: Burggraaf
authors: Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands.
authors: J
authors: J
authors: Stevens
mesh_terms: D000293:Adolescent; D000328:Adult; D059451:Biosimilar Pharmaceuticals / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013810:Therapeutic Equivalency; D000068878:Trastuzumab / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D059451:Biosimilar Pharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Biological; Biosimilarity; Non-linear kinetics; Pharmacokinetics; Population pharmacokinetic modelling; Trastuzumab