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Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn’s Disease

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Abstract

Background and Objectives

Infliximab is a monoclonal anti-tumor necrosis factor-α (anti-TNFα) antibody that profoundly modified the treatment of Crohn’s disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to infliximab in patients with CD. Our aim was to study its influence on infliximab pharmacokinetics and risk of relapse after infliximab discontinuation.

Methods

In 111 CD patients in remission, infliximab was discontinued and its concentrations were measured for 30 months or until relapse. Infliximab pharmacokinetics were described using monocompartmental population modeling.

Results

The elimination rate of infliximab increased with C-reactive protein (CRP) [p = 0.00018] and was 16 % higher in FCGR3A-158V/V patients than in F carriers (p = 0.0028). Risk of relapse was higher in patients with baseline CRP ≥5 mg/L than in those with a lower value (p = 0.0000029). In addition, there was a first-order interaction between CRP and the FCGR3A genotype; in patients with high CRP, risk of relapse was higher for V/V patients than for F carriers (hazard ratio 4.80 and 2.84 for V/V and F carriers, respectively; p = 0.013).

Conclusion

Both increased inflammation and FCGR3A-158V/V genotype are associated with increased infliximab elimination and risk of relapse after infliximab discontinuation in patients with CD.

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Acknowledgments

This work was a collaborative venture by GETAID (Groupe d’Étude Thérapeutique des Affections Inflammatoires du Tube Digestif). The following GETAID investigators participated in patient recruitment: Amiens (J.L. Dupas), Bordeaux (D. Laharie), Caen (J.M. Reimund), Clichy-Beaujon (Y. Bouhnik), Colombes – L Mourier (P. Jouet), Gent (M. De Vos), Liège (J. Belaiche, E. Louis), Lille (J.-F. Colombel, G. Vernier-Massouille), Lyon (S. Nancey), Marseille (J.C. Grimaud), Montpellier (M. Veyrac), Nantes (A. Boureille, M. Flamant), Paris – Hôpital Européen Georges Pompidou (R. Jian), Paris – Lariboisière (P. Marteau), Paris – St Louis (M. Lemann, M. Allez), Rouen (G. Savoye), Strasbourg (B. Duclos), and Tours (L. Picon). The authors would like to thank Jean-Yves Mary and Nicolas Azzopardi for statistical advice, Hervé Watier for scientific advice, Céline Desvignes for blood-sample management, Anne-Claire Duveau, Caroline Brochon, Audrey Farnault and Marie-Noëlle Marson for technical assistance with infliximab and ATI assays, and FCGR3A genotyping. The University Hospital of Tours received an FEDER (Fonds Européen de Développement Régional – European funding for regional development) for its CePiBAc (Cetre pilote de suivi biologique des anticorps thérapeutiques – Pilot centre for therapeutic antibodies monitoring). This work was partly supported by the French Higher Education and Research Ministry under the program ‘Investissements d’avenir’ Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01.

Disclosures

Jean-Frédéric Colombel has served as a consultant, advisory board member, or speaker for Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Merck & Co., Millenium Pharmaceuticals Inc., Nutrition Science Partners Ltd, Pfizer Inc., Prometheus Laboratories, Receptos, Sanofi, Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex, and Dr. August Wolff GmbH & Co. Matthieu Allez has served as a consultant for Abbott, UCB Pharma, Ferring, Merck Sharp and Dohme Corp., TcLand, TxCell, Novo Nordisk, Pfizer, and GlaxoSmithKline; has received lecture fees from Merck Sharp and Dohme Corp., Ferring, Neovacs, Janssen Cilag, and Abbott; and has received financial support for research from Novo Nordisk. Edouard Louis has received fees for the following: research grant from AstraZeneca, Schering-Plough, and Abbott; speaker fees from Abbott, Abbvie, AstraZeneca, Ferring, Schering-Plough, MSD, Chiesi, Menarini, Nycomed, Falk, UCB; advisory board fees from Abbott, Abbvie, Ferring, UCB, MSD, Millenium, Mitsubishi Pharma, Takeda; and consultant fees from Abbvie. Gilles Paintaud has been a consultant for Laboratoires Français du Fractionnement et des Biotechnologies (LFB) and Pierre-Fabre Laboratories; his research team has received finance from Roche Pharma, Chugai, Pfizer, Novartis and Janssen. David Ternant, Zahir Berkane, Laurence Picon, and Valérie Gouilleux-Gruart declare no conflicts of interest.

Authors’ responsibility

David Ternant, the corresponding author, confirms full access to all data in the study, and final responsibility.

Authors’ contributions

David Ternant, Zahir Berkane, Laurence Picon, Valérie Gouilleux-Gruart, Jean-Frédéric Colombel, Matthieu Allez, Edouard Louis, and Gilles Paintaud wrote the manuscript; Edouard Louis and Gilles Paintaud designed the research; David Ternant, Zahir Berkane, and Gilles Paintaud analyzed the data; and Valérie Gouilleux-Gruart performed the analytical part.

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Authors and Affiliations

  1. Université François Rabelais de Tours, CNRS UMR 7292, 2 Boulevard Tonnellé, 37044, Tours, CEDEX, France

    David Ternant, Zahir Berkane, Valérie Gouilleux-Gruart & Gilles Paintaud

  2. Laboratory of Pharmacology-Toxicology, CHRU de Tours, Tours, France

    David Ternant, Zahir Berkane & Gilles Paintaud

  3. Department of Gastroenterology, CHRU de Tours, Tours, France

    Laurence Picon

  4. Department of Immunology, CHRU de Tours, Tours, France

    Valérie Gouilleux-Gruart

  5. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jean-Frédéric Colombel

  6. Service de Gastroentérologie, INSERM Unit U940 (Avenir), Hôpital Saint-Louis, APHP, Université Denis Diderot, Paris, France

    Matthieu Allez

  7. University Hospital, CHU of Liège, Liège, Belgium

    Edouard Louis

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  1. David Ternant
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  2. Zahir Berkane
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Correspondence to David Ternant.

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Ternant, D., Berkane, Z., Picon, L. et al. Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn’s Disease. Clin Pharmacokinet 54, 551–562 (2015). https://doi.org/10.1007/s40262-014-0225-3

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