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Assessing the Impact of Immunogenicity and Improving Prediction of Trough Concentrations: Population Pharmacokinetic Modeling of Adalimumab in Patients with Crohn’s Disease and Ulcerative Colitis

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Abstract

Background and Objective

Predicting adalimumab pharmacokinetics (PK) for patients impacted by anti-drug antibodies (ADA) has been challenging. The present study assessed the performance of the adalimumab immunogenicity assays in predicting which patients with Crohn’s disease (CD) and ulcerative colitis (UC) have low adalimumab trough concentrations; and aimed to improve predictive performance of adalimumab population PK (popPK) model in CD and UC patients whose PK was impacted by ADA.

Methods

Adalimumab PK and immunogenicity data obtained from 1459 patients in SERENE CD (NCT02065570) and SERENE UC (NCT02065622) were analyzed. Adalimumab immunogenicity was assessed using electrochemiluminescence (ECL) and enzyme-linked immunosorbent (ELISA) assays. From these assays, three analytical approaches (ELISA concentrations, titer, and signal-to-noise [S/N] measurements) were tested as predictors for classifying patients with/without low concentrations potentially affected by immunogenicity. The performance of different thresholds for these analytical procedures was assessed using receiver operating characteristic curves and precision-recall curves. Based on the results from the most sensitive immunogenicity analytical procedure, patients were classified into PK-not-ADA-impacted and PK-ADA-impacted subpopulations. Stepwise popPK modeling was implemented to fit the PK data to an empirical adalimumab two-compartment model with linear elimination and ADA delay compartments to account for the time delay to generate ADA. Model performance was assessed by visual predictive checks and goodness-of-fit plots.

Results

The classical ELISA-based classification (with 20 ng/mL ADA as lower threshold) showed a good balance of precision and recall, to determine which patients had at least 30% adalimumab concentrations below 1 µg/mL. Titer-based classification with the lower limit of quantitation (LLOQ) as threshold showed higher sensitivity to classify these patients compared to the ELISA-based approach. Therefore, patients were classified as PK-ADA-impacted or PK-not-ADA impacted using the LLOQ titer threshold. In the stepwise modeling approach ADA-independent parameters were first fit using PK data from titer-PK-not-ADA-impacted population. The identified ADA-independent covariates included the effect of indication, weight, baseline fecal calprotectin, baseline C-reactive protein, baseline albumin on clearance; and sex and weight on volume of distribution of the central compartment. Pharmacokinetic-ADA-driven dynamics were characterized using PK data for the PK-ADA-impacted population. The categorical covariate based on the ELISA classification was the best at describing the additional effect of immunogenicity analytical approaches on ADA synthesis rate. The model was able to adequately describe the central tendency and variability for PK-ADA-impacted CD/UC patients.

Conclusions

The ELISA assay was found to be optimal for capturing impact of ADA on PK. The developed adalimumab popPK model is robust in predicting PK profiles for CD and UC patients whose PK was impacted by ADA.

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Acknowledgements

Medical writing support was provided by Mia DeFino, MS, ELS, a freelance medical writer under contract with AbbVie. Programming support was provided by Rainer Hans Krauss. Peter Noertersheuser contributed modeling ideas for the impact of immunogenicity on PK.

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Authors and Affiliations

  1. AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany

    Ana Victoria Ponce-Bobadilla, Sven Stodtmann, Insa Winzenborg, Sven Mensing, Jonas Blaes, Tobias Haslberger, Loic Laplanche & Ingeborg Dreher

  2. AbbVie, 1 N. Waukegan Road, North Chicago, IL, 60064, USA

    Mong-Jen Chen & Nael M. Mostafa

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  1. Ana Victoria Ponce-Bobadilla
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Corresponding author

Correspondence to Nael M. Mostafa.

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Conflict of interest

All authors are employees at AbbVie and may hold AbbVie stock.

Funding

AbbVie provided financial support for the studies and participated in the study design, study conduct, and analysis and interpretation of data and the writing, review, and approval of the manuscript.

Ethics approval

The studies were conducted in accordance with Good Clinical Practice Guidelines and the ethical principles that have their origin in the Declaration of Helsinki. The protocols were approved by the institutional review board or ethics committee for each site.

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Each subject provided written informed consent before any study-related procedures were performed.

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All authors provided consent for publication.

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AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.

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Author contributions

AVPB, MJC, and SS wrote the manuscript. AVPB, MJC, SS, NM, IW, SM, JB, TH, and ID analyzed data, performed research, and contributed new analytical tools. AVPB, SS, NM, JB, TH, and ID designed research. LL supervised analysis and research for both studies.

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Ponce-Bobadilla, A.V., Stodtmann, S., Chen, MJ. et al. Assessing the Impact of Immunogenicity and Improving Prediction of Trough Concentrations: Population Pharmacokinetic Modeling of Adalimumab in Patients with Crohn’s Disease and Ulcerative Colitis. Clin Pharmacokinet 62, 623–634 (2023). https://doi.org/10.1007/s40262-023-01221-x

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  • DOI: https://doi.org/10.1007/s40262-023-01221-x

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