Magnitude of Increased Infliximab Clearance Imposed by Anti-infliximab Antibodies in Crohn’s Disease Is Determined by Their Concentration

Abstract

Antibodies (Abs) against infliximab (IFX) increase IFX clearance and can result in treatment failure and acute hypersensitivity reactions. However, interpretation of their clinical value is complicated by individual differences in Ab responses and methods used for quantification. The increase in IFX clearance imposed by anti-IFX Abs has generally been evaluated using a binary classification, i.e., positive or negative. This analysis aimed to investigate if anti-IFX Ab concentrations provide a more adequate prediction of alterations in clearance. Data originated from a clinical trial on Crohn’s disease patients with IFX treatment failure. The trial was not originally designed for pharmacokinetic analysis. Therefore, published pharmacokinetic models were utilized as priors to enable covariate investigation. The impact of anti-IFX Abs on clearance was assessed using different mathematical relationships and exploiting information from two different quantification assays, measuring semi-quantitative “total” or “unbound neutralizing” concentrations of anti-IFX Ab, respectively. Inclusion of anti-IFX Ab status/concentration improved the model’s performance for all investigated relationships. The anti-IFX Ab concentrations were superior to the binary classifications, indicating that the magnitude of increase in IFX clearance imposed by anti-IFX Abs closely relates to their concentration. Furthermore, total anti-IFX Ab concentrations appeared superior to the unbound neutralizing fraction in identifying high clearance individuals. Simulations showed that even at low concentrations, anti-IFX Abs lead to sub-therapeutic IFX concentrations, supporting a need of treatment interventions in all anti-IFX Ab positive patients. The developed model can serve as a basis for further investigations to refine treatment recommendations for patients with anti-IFX Abs.

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Abbreviations

Ab:

Antibody

Anti-IFX Abs (+/−):

Anti-infliximab antibodies (positive/negative)

IFX:

Infliximab

IBD:

Inflammatory bowel disease

HMSA:

Homogenous mobility shift assay

(>/<) LLOQ:

(Above/below) lower limit of quantification

mAb:

Monoclonal antibody

RGA:

Reporter gene assay

TNFα:

Tumor necrosis factor α

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Acknowledgments

The authors would like to thank Eurodiagnostica (Malmö, Sweden) and Prometheus Laboratories Inc. (San Diego, CA, USA).

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Correspondence to Charlotte Kloft.

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Helena Edlund and Casper Steenholdt contributed equally to this work.

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Edlund, H., Steenholdt, C., Ainsworth, M.A. et al. Magnitude of Increased Infliximab Clearance Imposed by Anti-infliximab Antibodies in Crohn’s Disease Is Determined by Their Concentration. AAPS J 19, 223–233 (2017). https://doi.org/10.1208/s12248-016-9989-8

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KEY WORDS

  • anti-drug antibodies
  • Crohn’s disease
  • frequentist’s prior model
  • infliximab
  • population pharmacokinetic modeling