Use of population approach non-linear mixed effects models in the evaluation of biosimilarity of monoclonal antibodies.

ABSTRACT

PURPOSE: 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.