Skip to main content
SpringerLink
Log in

Model-Based Therapeutic Drug Monitoring of Infliximab Using a Single Serum Trough Concentration

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348(7):601–8.

    Article  PubMed  CAS  Google Scholar 

  2. Krzysiek R, Breban M, Ravaud P, et al. Circulating concentration of infliximab and response to treatment in ankylosing spondylitis: results from a randomized control study. Arthritis Rheumatol. 2009;61(5):569–76.

    Article  Google Scholar 

  3. Passot C, Mulleman D, Bejan-Angoulvant T, et al. The underlying inflammatory chronic disease influences infliximab pharmacokinetics. MAbs. 2016;8(7):1407–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet. 2005;366(9494):1367–74.

    Article  PubMed  CAS  Google Scholar 

  5. St Clair EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2002;46(6):1451–9.

    Article  CAS  Google Scholar 

  6. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheumatol. 1998;41(9):1552–63.

    Article  CAS  Google Scholar 

  7. Mulleman D, Lin DCM, Ducourau E, et al. Trough infliximab concentrations predict efficacy and sustained control of disease activity in rheumatoid arthritis. Ther Drug Monit. 2010;32(2):232–6.

    PubMed  CAS  Google Scholar 

  8. Mulleman D, Meric JC, Paintaud G, et al. Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis. Arthritis Res Ther. 2009;11(6):R178 epub 2009 Nov 25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wolbink GJ, Voskuyl AE, Lems WF, et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2005;64(5):704–7.

    Article  PubMed  CAS  Google Scholar 

  10. Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4(10):1248–54 epub 2006 Aug 22.

    Article  PubMed  CAS  Google Scholar 

  11. van den Bemt BJ, den Broeder AA, Wolbink GJ, et al. The combined use of disease activity and infliximab serum trough concentrations for early prediction of (non-)response to infliximab in rheumatoid arthritis. Br J Clin Pharmacol. 2013;76(6):939–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut. 2014;63(11):1721–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014;147(6):1296–307.

    Article  PubMed  CAS  Google Scholar 

  14. Steenholdt C, Brynskov J, Thomsen OO, et al. Individualized therapy is a long-term cost-effective method compared to dose intensification in Crohn’s disease patients failing infliximab. Dig Dis Sci. 2015;60(9):2762–70.

    Article  PubMed  CAS  Google Scholar 

  15. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320–9.

    Article  PubMed  CAS  Google Scholar 

  16. Medina F, Plasencia C, Goupille P, et al. Current practice for therapeutic drug monitoring of biopharmaceuticals in rheumatoid arthritis. Ther Drug Monit. 2017;39(4):364–9.

    Article  PubMed  CAS  Google Scholar 

  17. Brandse JF, Mould D, Smeekes O, et al. A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(4):650–60.

    Article  PubMed  Google Scholar 

  18. Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20(12):2247–59.

    Article  PubMed  Google Scholar 

  19. Mould DR, Dubinsky MC. Dashboard systems: pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies. J Clin Pharmacol. 2015;2015(55 Suppl. 3):S51–9.

    Article  CAS  Google Scholar 

  20. Aubourg A, Picon L, Lecomte T, et al. A robust estimation of infliximab pharmacokinetic parameters in Crohn’s disease. Eur J Clin Pharmacol. 2015;71(12):1541–2.

    Article  PubMed  Google Scholar 

  21. Bejan-Angoulvant T, Ternant D, Daoued F, et al. Brief report: relationship between serum infliximab concentrations and risk of infections in patients treated for spondyloarthritis. Arthritis Rheumatol. 2017;69(1):108–13.

    Article  PubMed  CAS  Google Scholar 

  22. Ternant D, Aubourg A, Magdelaine-Beuzelin C, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit. 2008;30(4):523–9. https://doi.org/10.1097/FTD.0b013e318180e300.

    Article  PubMed  CAS  Google Scholar 

  23. Ternant D, Mulleman D, Degenne D, et al. An enzyme-linked immunosorbent assay for therapeutic drug monitoring of infliximab. Ther Drug Monit. 2006;28(2):169–74.

    Article  PubMed  CAS  Google Scholar 

  24. Ternant D, Ducourau E, Perdriger A, et al. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. Br J Clin Pharmacol. 2014;78(1):118–28.

    Article  PubMed  CAS  Google Scholar 

  25. Ternant D, Mulleman D, Lauféron F, et al. Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis. Br J Clin Pharmacol. 2011;73(1):55–65.

  26. Passot C, Pouw MF, Mulleman D, et al. Therapeutic drug monitoring of biopharmaceuticals may benefit from pharmacokinetic and pharmacokinetic-pharmacodynamic modeling. Ther Drug Monit. 2017;39(4):322–6.

    Article  PubMed  CAS  Google Scholar 

  27. Fasanmade AA, Adedokun OJ, Blank M, et al. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011;33(7):946–64.

    Article  PubMed  CAS  Google Scholar 

  28. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol. 2009;65(12):1211–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Xu Z, Seitz K, Fasanmade A, et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol. 2008;48(6):681–95.

    Article  PubMed  CAS  Google Scholar 

  30. Benkali K, Premaud A, Picard N, et al. Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients. Clin Pharmacokinet. 2009;48(12):805–16. https://doi.org/10.2165/11318080-000000000-00000.

    Article  PubMed  CAS  Google Scholar 

  31. Kassir N, Labbe L, Delaloye JR, et al. Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients. Br J Clin Pharmacol. 2014;77(6):1051–63.

    Article  PubMed  CAS  Google Scholar 

  32. Thomson AH, Whiting B. Bayesian parameter estimation and population pharmacokinetics. Clin Pharmacokinet. 1992;22(6):447–67.

    Article  PubMed  CAS  Google Scholar 

  33. Zhao W, Elie V, Baudouin V, et al. Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome. Br J Clin Pharmacol. 2010;69(4):358–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Dreesen E, Gils A, Vermeire S. Pharmacokinetic modeling and simulation of biologicals in inflammatory bowel disease: the dawning of a new era for personalized treatment. Curr Drug Targets. (epub 2016 Mar 7).

  35. Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods. J Pharm Sci. 1982;71(12):1344–8.

    Article  PubMed  CAS  Google Scholar 

  36. Yamamoto T, Terakawa H, Hisaka A, et al. Bayesian estimation of pharmacokinetic parameters of vancomycin in patients with decreasing renal function. J Pharm Sci. 2012;101(8):2968–75.

    Article  PubMed  CAS  Google Scholar 

  37. FDA. Guidance for industry: population pharmacokinetics. Rockville (MD): CDER; 1999. https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf. Accessed 1 Jun 2017.

  38. Mulleman D, Ducourau E, Paintaud G, et al. Should anti-TNF-alpha drug levels and/or anti-drug antibodies be assayed in patients treated for rheumatoid arthritis? Jt Bone Spine. 2012;79(2):109–12.

    Article  Google Scholar 

  39. Papamichael K, Gils A, Rutgeerts P, et al. Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: evolution in the definition and management of primary nonresponse. Inflamm Bowel Dis. 2015;21(1):182–97.

    Article  PubMed  Google Scholar 

  40. 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. 2015;54(5):551–62.

    Article  PubMed  CAS  Google Scholar 

  41. Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63(8):1258–64.

    Article  PubMed  CAS  Google Scholar 

  42. Ng CM, Loyet KM, Iyer S, et al. Modeling approach to investigate the effect of neonatal Fc receptor binding affinity and anti-therapeutic antibody on the pharmacokinetic of humanized monoclonal anti-tumor necrosis factor-alpha IgG antibody in cynomolgus monkey. Eur J Pharm Sci. 2014;51:51–8.

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, CNRS, UMR 7292, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France

    David Ternant, Christophe Passot, Philippe Goupille, Céline Desvignes, Thierry Lecomte, Denis Mulleman & Gilles Paintaud

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

    David Ternant, Christophe Passot, Céline Desvignes & Gilles Paintaud

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

    Alexandre Aubourg, Laurence Picon & Thierry Lecomte

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

    Philippe Goupille & Denis Mulleman

Authors
  1. David Ternant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christophe Passot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandre Aubourg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Philippe Goupille
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Céline Desvignes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laurence Picon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thierry Lecomte
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Denis Mulleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gilles Paintaud
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to David Ternant.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-017-0621-6

Search

Navigation