The Utility of Modeling and Simulation Approaches to Evaluate Immunogenicity Effect on the Therapeutic Protein Pharmacokinetics

Abstract

Abstract. While therapeutic proteins (TP), particularly recombinant human proteins and fully human monoclonal antibodies, are designed to have a low immunogenic potential in humans, a clinical immune response does sometimes occur and cannot be predicted from preclinical studies. Changes in TP pharmacokinetics may be perceived as an early indication of antibody formation and serve as a surrogate for later changes in efficacy and safety in individual subjects. Given the substantial increase in number of biological products, including biosimilars, there is an urgent need to quantitatively predict and quantify the immune response and any consequential changes in TP pharmacokinetics. The purpose of this communication is to review the utility of population-based modeling and simulation approaches developed to date for investigating the development of an immune response and assessing its impact on TP pharmacokinetics. Two examples of empirical modeling approaches for pharmacokinetic assessment are presented. The first example presents methods to analyze pharmacokinetic data in the presence of anti-drug antibody (ADA) and confirm the effect of immunogenicity on TP pharmacokinetics in early phases of drug development. The second example provides a framework to analyze pharmacokinetic data in the absence or with very low incidence of ADA and confirm with enough power the lack of an immunogenicity effect on TP pharmacokinetics in late phases of drug development. Finally, a theoretical mechanism-based modeling framework is presented to mathematically relate the complex interaction among TP, their targets, and ADA.

A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

“…As mentioned in the "Introduction," similar model structures were proposed recently by Chirmule et al (1) and Perez Ruixo et al (21) independently to evaluate the effect of immunogenicity on therapeutic protein pharmacokinetics. Similar to the above two models, the PK/ADA model is also based on the assumption that the drug disposition can be affected by ADA-mediated clearance.…”

“…In this article, we are proposing a PK/ADA mathematical modeling approach for quantitatively assessing ADA response. Recently, similar basic model structures were proposed by Chirmule et al and Perez Ruixo et al to evaluate the impact of immunogenicity on therapeutic protein pharmacokinetics (1,21). However, this paper applies a fully developed mathematical model to data fitting and simulation.…”

A White Paper—Consensus and Recommendations of a Global Harmonization Team on Assessing the Impact of Immunogenicity on Pharmacokinetic Measurements

“…We have cited numerous papers that delve into the pharmacometrics approaches (47,62,63) and recommend Kelley et al (64) as relevant nonclinical reading. Although specific requirements have not been addressed in any regulatory guidance issued to date, it is clear that regulator expectations regarding the understanding of the impact of anti-drug antibodies on PK assays are evolving.…”

Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins

“…The in-depth delineation of this interplay between ADA and PK interactions that can have a significant clinical impact is still evolving. Recent work from other groups has also demonstrated ADA-mediated clearance as a covariate in PK models (3,(6)(7)(8)(9)(10)(11)(12).…”