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

Abstract

Abstract. A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADAmediated drug clearance, the model provides an approach to characterize ADA generation during the study, including the maximum ADA response, sensitivity of ADA response to drug dose level, affinity maturation rate, time lag to observe an ADA response, and the elimination rate for ADA-drug complex. The model also provides a mean to estimate putative concentration-time profiles for ADA, ADA-drug complex, and ADA binding affinity-time profile. When simulating ADA responses to various drug dose levels, bell-shaped dose-response curves were generated. The model contains simultaneous quantitative modeling and provides estimation of the characteristics of therapeutic protein drug PK and ADA responses in vivo. With further experimental validation, the model may be applied to the simulation of ADA response to therapeutic protein drugs in silico, or be applied in subsequent PK/PD models.

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

“…A third component built into the model to assess the impact of ADA on PK was the impact of various factors that contribute to the impact on exposure. Immune response to a TP is interplay of several factors that include cells involved in antigen processing, sequence of proteins, genetic and diseased state of individuals, and concomitant medications (7)(8)(9). In this study, animal weights, time of administration, and other demographic parameters were included along with real time PK data from preclinical studies.…”

“…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).…”

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.…”

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

“…In T‐cell independent B cell activation mechanism, the antigens (known as thymus‐independent antigens) with their repetitive structure make cross‐linking of the B‐cell receptors and elicit B cell activation. The repetitive structure of the antigen may arise due to aggregation 84. In T‐cell dependent activation mechanism, activated T cells may directly bind to B cells forming immunological synapses or secrete stimulatory cytokines (IL‐4, IL‐5, etc.)…”