Abstract
Background and Objectives
The pharmacokinetics of infliximab are highly variable and influence clinical response in chronic inflammatory diseases. The goal of this study was to build a Bayesian model allowing predictions of upcoming infliximab concentrations and dosing regimen adjustment, using only one concentration measurement and information regarding the last infliximab infusion.
Methods
This retrospective study was based on data from 218 patients treated with infliximab in Tours University Hospital who were randomly assigned to learning (two-thirds) or validation (one-third) data subsets. One-compartment pharmacokinetic and time since last dose (TLD) models were built and compared using learning and validation subsets. From these models, Bayesian pharmacokinetic and TLD models using one concentration measurement (1C-PK and 1C-TLD) were designed. The predictive performances of the 1C-TLD model were tested on two external validation cohorts.
Results
Pharmacokinetic and TLD models described the data satisfactorily and provided accurate parameter estimations. Comparable predictions of infliximab concentrations were obtained from pharmacokinetic versus TLD models, as well as from Bayesian 1C-PK versus 1C-TLD models. The 1C-TLD model showed satisfactory prediction of future infliximab concentrations and provided satisfactory predictions of infliximab steady-state concentration for up to three upcoming visits after a blood sample.
Conclusions
Accurate individual concentration predictions can be obtained using a single infliximab concentration measurement and information regarding only the last infusion. The 1C-TLD model may help to optimize the dosing regimen of infliximab in routine therapeutic drug monitoring.
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Acknowledgements
The authors thank Drs. Saloua Mammou, Stéphanie Willot, Mahtab Samimi, and Annabel Maruani for patient follow-up; Anne-Claire Duveau and Caroline Guerineau-Brochon for technical assistance with infliximab assays; and the medical staff and nurses from the Rheumatology, Gastroenterology, Dermatology, and Paediatrics departments.
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Contributions
DT analyzed and interpreted the data, and wrote the manuscript. CP participated in the data conception, analysis, and interpretation and reviewed the manuscript. TL participated in data conception and interpretation, and reviewed the manuscript. CD participated in data conception and reviewed the manuscript. NA participated in data analysis and reviewed the manuscript. AA, LP, and PG participated in data acquisition and reviewed the manuscript. DM participated in data acquisition and interpretation, and reviewed the manuscript. GP supervised the study, participated in the writing of the manuscript, and reviewed the manuscript.
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Ethical Approval and Informed Consent
Ethical approval and informed consent were not sought in this retrospective analysis of routine patients, which is in accordance with institutional guidelines.
Funding
Measurements of infliximab serum concentrations were carried out within the CePiBAc (Centre Pilote de suivi Biologique des traitements par Anticorps) platform, which was co-financed by the European Union and the European Regional Development Fund. 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). CNRS UMR 7292 participates in the Monitoring of monoclonal Antibodies Group in Europe (MAGE) Consortium for inflammatory diseases. The MAGE Consortium is supported by LE STUDIUM Loire Valley Institute for Advanced Studies (http://www.lestudium-ias.com).
Conflict of interest
David Ternant has given lectures on behalf of his institution for Amgen and Sanofi. Alexandre Aubourg has acted as a consultant for MSD, Abbvie, Takeda, and Janssen. He has also received support for travel by MSD, Ferring, and Abbvie. Philippe Goupille has been a consultant for Abbvie, Biogaran, BMS, Celgene, Janssen, MSD, Novartis, Pfizer, and UCB; he has participated on behalf of his institution in clinical trials sponsored by Abbvie, Biogaran, BMS, Boehringer, Janssen, Lilly, MSD, Novartis, Pfizer, and UCB. Denis Mulleman has participated on behalf of his institution in clinical trials sponsored by Abbott, Roche, BMS, Pfizer, UCB, and MSD; his hospital department received a grant for research from Abbott in 2004 and from Nordic Pharma in 2012; he has acted as a consultant and given lectures on behalf of his institution for MSD and Pfizer; and he has been invited to attend international congresses by MSD, Roche, BMS, Abbott, and Janssen-Cilag. Gilles Paintaud has received grants for his research team from Roche Pharma, Chugai, Pfizer, Novartis, and Sanofi-Genzyme. Christophe Passot, Thierry Lecomte, Laurence Picon, and Céline Desvignes have nothing to declare.
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Ternant, D., Passot, C., Aubourg, A. et al. Model-Based Therapeutic Drug Monitoring of Infliximab Using a Single Serum Trough Concentration. Clin Pharmacokinet 57, 1173–1184 (2018). https://doi.org/10.1007/s40262-017-0621-6
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DOI: https://doi.org/10.1007/s40262-017-0621-6