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Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

  • Research Article
  • Theme: Impact of Immunogenicity on PK/PD of Protein Therapeutics
  • Published:
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Abstract

The availability of highly sensitive immunoassays enables the detection of antidrug antibody (ADA) responses of various concentrations and affinities. The analysis of the impact of antibody status on drug pharmacokinetics (PK) is confounded by the presence of low-affinity or low-concentration antibody responses within the dataset. In a phase 2 clinical trial, a large proportion of subjects (45%) developed ADA following weekly dosing with AMG 317, a fully human monoclonal antibody therapeutic. The antibody responses displayed a wide range of relative concentrations (30 ng/mL to >13 μg/mL) and peaked at various times during the study. To evaluate the impact of immunogenicity on PK, AMG 317 concentration data were analyzed following stratification by dose group, time point, antibody status (positive or negative), and antibody level (relative concentration). With dose group as a stratifying variable, a moderate reduction in AMG 317 levels (<50%) was observed in antibody-positive subjects when compared to antibody-negative subjects, but the difference was not statistically significant in all dose groups. The most significant reduction in AMG 317 levels was revealed when antibody data was stratified by both time point and antibody level. In general, high ADA concentrations (>500 ng/mL) and later time points (week 12) were associated with significantly (up to 97%) lower trough AMG 317 concentrations. The use of quasi-quantitative antibody data and appropriate statistical methods was critical for the most comprehensive evaluation of the impact of immunogenicity on PK.

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ACKNOWLEDGMENTS

We thank Alex Colbert for coordinating the drug concentration assays and sample analysis and Mike Hale for the statistical advice. Support for the study was provided by Amgen Inc. All authors are employees and shareholders of the study sponsor.

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Authors and Affiliations

  1. Clinical Immunology, Amgen Inc., Thousand Oaks, California, 91320, USA

    Sarah A. Hoofring, Steven J. Swanson, Narendra Chirmule & Marta Starcevic

  2. Biostatistics–Medical Sciences, Amgen Inc., Thousand Oaks, California, 91320, USA

    Lei Zhou & Yu Wu

  3. Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, 91320, USA

    Thuy Vu & Peiming Ma

Authors
  1. Lei Zhou
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  2. Sarah A. Hoofring
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  3. Yu Wu
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  4. Thuy Vu
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  6. Steven J. Swanson
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Correspondence to Marta Starcevic.

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Guest Editors: Bernd Meibohm and Naren Chirmule

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Zhou, L., Hoofring, S.A., Wu, Y. et al. Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics. AAPS J 15, 30–40 (2013). https://doi.org/10.1208/s12248-012-9408-8

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  • DOI: https://doi.org/10.1208/s12248-012-9408-8

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