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

Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 4

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 ADA-mediated 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.

Authors and Affiliations

Xiaoying Chen, Timothy Hickling, Eugenia Kraynov, Bing Kuang, Chuenlei Parng, Paolo Vicini

Keywords

Related Articles

Diurnal Variation in P-glycoprotein-Mediated Transport and Cerebrospinal Fluid Turnover in the Brain

The online version of this article (doi:10.1208/s12248-014-9625-4) contains supplementary material, which is available to authorized users.

Theoretical Considerations and Practical Approaches to Address the Effect of Anti-drug Antibody (ADA) on Quantification of Biotherapeutics in Circulation

Continuous improvement in bioanalytical method development is desired in order to ensure the quality of the data and to better support pharmacokinetic (PK) and safety studies of biotherapeutics. One area that has been ge...

Model-based development of gemcabene, a new lipid-altering agent

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent. The decisions were driven by a model of the likely clini...

Biomarkers, metabonomics, and drug development: Can inborn errors of metabolism help in understanding drug toxicity?

Application of “omics” technology during drug discovery and development is rapidly evolving. This review evaluates the current status and future role of “metabonomics” as a tool in the dru...

Structure-Based Prediction of the Nonspecific Binding of Drugs to Hepatic Microsomes

For the accurate prediction of in vivo hepatic clearance or drug–drug interaction potential through in vitro microsomal metabolic data, it is essential to evaluate the fraction unbound in hepatic microsomal incub...

Download PDF file
  • EP ID EP681172
  • DOI  10.1208/s12248-013-9517-z
  • Views 71
  • Downloads 0

How To Cite

Xiaoying Chen, Timothy Hickling, Eugenia Kraynov, Bing Kuang, Chuenlei Parng, Paolo Vicini (2013). A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics. The AAPS Journal, 15(4), -. https://europub.co.uk/articles/-A-681172