The AAPS Journal

, Volume 19, Issue 1, pp 223–233 | Cite as

Magnitude of Increased Infliximab Clearance Imposed by Anti-infliximab Antibodies in Crohn’s Disease Is Determined by Their Concentration

  • Helena Edlund
  • Casper Steenholdt
  • Mark A. Ainsworth
  • Eva Goebgen
  • Jørn Brynskov
  • Ole Ø. Thomsen
  • Wilhelm Huisinga
  • Charlotte Kloft
Research Article

Abstract

Antibodies (Abs) against infliximab (IFX) increase IFX clearance and can result in treatment failure and acute hypersensitivity reactions. However, interpretation of their clinical value is complicated by individual differences in Ab responses and methods used for quantification. The increase in IFX clearance imposed by anti-IFX Abs has generally been evaluated using a binary classification, i.e., positive or negative. This analysis aimed to investigate if anti-IFX Ab concentrations provide a more adequate prediction of alterations in clearance. Data originated from a clinical trial on Crohn’s disease patients with IFX treatment failure. The trial was not originally designed for pharmacokinetic analysis. Therefore, published pharmacokinetic models were utilized as priors to enable covariate investigation. The impact of anti-IFX Abs on clearance was assessed using different mathematical relationships and exploiting information from two different quantification assays, measuring semi-quantitative “total” or “unbound neutralizing” concentrations of anti-IFX Ab, respectively. Inclusion of anti-IFX Ab status/concentration improved the model’s performance for all investigated relationships. The anti-IFX Ab concentrations were superior to the binary classifications, indicating that the magnitude of increase in IFX clearance imposed by anti-IFX Abs closely relates to their concentration. Furthermore, total anti-IFX Ab concentrations appeared superior to the unbound neutralizing fraction in identifying high clearance individuals. Simulations showed that even at low concentrations, anti-IFX Abs lead to sub-therapeutic IFX concentrations, supporting a need of treatment interventions in all anti-IFX Ab positive patients. The developed model can serve as a basis for further investigations to refine treatment recommendations for patients with anti-IFX Abs.

KEY WORDS

anti-drug antibodies Crohn’s disease frequentist’s prior model infliximab population pharmacokinetic modeling 

Abbreviations

Ab

Antibody

Anti-IFX Abs (+/−)

Anti-infliximab antibodies (positive/negative)

IFX

Infliximab

IBD

Inflammatory bowel disease

HMSA

Homogenous mobility shift assay

(>/<) LLOQ

(Above/below) lower limit of quantification

mAb

Monoclonal antibody

RGA

Reporter gene assay

TNFα

Tumor necrosis factor α

Notes

Acknowledgments

The authors would like to thank Eurodiagnostica (Malmö, Sweden) and Prometheus Laboratories Inc. (San Diego, CA, USA).

Supplementary material

12248_2016_9989_MOESM1_ESM.docx (658 kb)
ESM 1 (DOCX 657 kb)

References

  1. 1.
    Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59. doi: 10.2165/11535960-000000000-0000.CrossRefPubMedGoogle Scholar
  2. 2.
    Tabrizi MA, Tseng CML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8. doi: 10.1016/S1359-6446(05)03638-X.CrossRefPubMedGoogle Scholar
  3. 3.
    Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91:635–46. doi: 10.1038/clpt.2011.328.CrossRefPubMedGoogle Scholar
  4. 4.
    Fasanmade AA, Adedokun OJ, Ford J, Hernandez D, Johanns J, Hu C, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol. 2009;65(12):1211–28. doi: 10.1007/s00228-009-0718-4.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. 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;33:946–64. doi: 10.1016/j.clinthera.2011.06.002.CrossRefPubMedGoogle Scholar
  6. 6.
    Dotan I, Ron Y, Yanai H, Becker S, Fishman S, Yahav L, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:2247–59. doi: 10.1097/MIB.0000000000000212.CrossRefPubMedGoogle Scholar
  7. 7.
    Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108:40–7. doi: 10.1038/ajg.2012.363.CrossRefPubMedGoogle Scholar
  8. 8.
    De Groot AS, Scott DW. Immunogenicity of protein therapeutics. Trends Immunol. 2007;28:482–90. doi: 10.1016/j.it.2007.07.011.CrossRefPubMedGoogle Scholar
  9. 9.
    Niebecker R, Kloft C. Safety of therapeutic monoclonal antibodies. Curr Drug Saf. 2010;5:275–86. doi: 10.2174/157488610792246055.CrossRefPubMedGoogle Scholar
  10. 10.
    Baert F, Noman M, Vermeire S, Van Assche G, D’Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–8. doi: 10.1056/NEJMoa020888.CrossRefPubMedGoogle Scholar
  11. 11.
    Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248–54. doi: 10.1016/j.cgh.2006.06.025.CrossRefPubMedGoogle Scholar
  12. 12.
    Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59:49–54. doi: 10.1136/gut.2009.183095.CrossRefPubMedGoogle Scholar
  13. 13.
    Dreesen E, Vande Casteele N, Tops S, Vermeire S, Gils A. Anti-drug antibodies, low serum albumin and high C-reactive protein increase infliximab clearance in patients with inflammatory bowel disease: a population pharmacokinetic study of the TAXIT trial. PAGE 25. 2016 Abstr 5873. www.page-meeting.org/?abstract=5873 Accessed 01 Jul 2016.
  14. 14.
    Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol. 2011;34:51–8. doi: 10.1111/j.1365-2036.2011.04682.x.CrossRefGoogle Scholar
  15. 15.
    Bendtzen K, Ainsworth MA, Steenholdt C, Thomsen OØ, Brynskov J. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies. Scand J Gastroenterol. 2009;44:774–81. doi: 10.1080/00365520802699278.CrossRefPubMedGoogle Scholar
  16. 16.
    Afif W, Loftus EV, Faubion WA, Kane SV, Bruining DH, Hanson KA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:1133–9. doi: 10.1038/ajg.2010.9.CrossRefPubMedGoogle Scholar
  17. 17.
    Velayos F, Kahn J, Sandborn W, Feagan B. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013;11:654–66. doi: 10.1016/j.cgh.2012.12.035.CrossRefPubMedGoogle Scholar
  18. 18.
    Steenholdt C, Brynskov J, Thomsen OØ, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919–27. doi: 10.1136/gutjnl-2013-305279.CrossRefPubMedGoogle Scholar
  19. 19.
    Steenholdt C, Brynskov J, Thomsen OØ, Munck L, Fallingborg J, Christensen L, 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;60:2762–70. doi: 10.1007/s10620-015-3581-4.CrossRefPubMedGoogle Scholar
  20. 20.
    Yanai H, Lichtenstein L, Assa A, Mazor Y, Weiss B, Levine A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522–30. doi: 10.1016/j.cgh.2014.07.029.CrossRefPubMedGoogle Scholar
  21. 21.
    Steenholdt C, Bendtzen K, Brynskov J, Ainsworth MA. Optimizing treatment with TNF-inhibitors in inflammatory bowel disease by monitoring drug levels and anti-drug antibodies. Inflamm Bowel Dis. 2016. doi:  10.1097/MIB.0000000000000772.
  22. 22.
    Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J. 2014;16:658–73. doi: 10.1208/s12248-014-9599-2.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ungar B, Chowers Y, Yavzori M, Picard O, Fudim E, Har-Noy O, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63:1258–64. doi: 10.1136/gutjnl-2013-305259.CrossRefPubMedGoogle Scholar
  24. 24.
    Steenholdt C, Al-khalaf M, Brynskov J, Bendtzen K, Thomsen OØ, Ainsworth MA. Clinical implications of variations in anti-infliximab antibody levels in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2209–17. doi: 10.1002/ibd.22910.CrossRefPubMedGoogle Scholar
  25. 25.
    Steenholdt C, Frederiksen MT, Bendtzen K, Ainsworth MA, Thomsen OØ, Brynskov J. Time course and clinical implications of development of antibodies against adalimumab in patients with inflammatory bowel disease. J Clin Gastroenterol. 2015;50:483–9. doi: 10.1097/MCG.0000000000000375.CrossRefGoogle Scholar
  26. 26.
    Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Munck LK, Christensen LA, et al. Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn’s disease. J Crohn’s Colitis. 2015;9:238–45. doi: 10.1093/ecco-jcc/jjv004.CrossRefGoogle Scholar
  27. 27.
    Vande Casteele N, Gils A, Singh S, Ohrmund L, Hauenstein S, Rutgeerts P, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108:962–71. doi: 10.1038/ajg.2013.12.CrossRefPubMedGoogle Scholar
  28. 28.
    Steenholdt C. Transient and persistent antibodies against TNF-inhibitors in IBD. Am J Gastroenterol. 2015;110:1623–4. doi: 10.1038/ajg.2015.325.CrossRefPubMedGoogle Scholar
  29. 29.
    Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 2012;14:296–302. doi: 10.1208/s12248-012-9340-y.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    U.S. Food and Drug Administration, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. Guidance for industry: immunogenicity assessment for therapeutic protein products. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338856.pdf. Accessed 01 Jul 2016.
  31. 31.
    Butler JE, Feldbush TL, McGivern PL, Stewart N. The enzyme-linked immunosorbent assay (ELISA): a measure of antibody concentration or affinity? Mol Immunol. 1978;15:131–6. doi: 10.1016/0161-5890(78)90053-6.Google Scholar
  32. 32.
    Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis. 2013;72:165–78. doi: 10.1136/annrheumdis-2012-202545.CrossRefPubMedGoogle Scholar
  33. 33.
    Xu Z, Seitz K, Fasanmade A, Ford J, Williamson P, Xu W, et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol. 2008;48:681–95. doi: 10.1177/0091270008316886.CrossRefPubMedGoogle Scholar
  34. 34.
    Ternant D, Aubourg A, Magdelaine-Beuzelin C, Degenne D, Watier H, Picon L, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit. 2008;30:523–9. doi: 10.1097/FTD.0b013e318180e300.PubMedGoogle Scholar
  35. 35.
    Buurman DJ, Maurer JM, Keizer RJ, Kosterink JG, Dijkstra G. Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice. Aliment Pharmacol Ther. 2015;42:529–39. doi: 10.1111/apt.1329.CrossRefPubMedGoogle Scholar
  36. 36.
    Gobburu JV. Pharmacometrics 2020. J Clin Pharmacol. 2010;50:151S–7. doi: 10.1177/009127001037697.CrossRefPubMedGoogle Scholar
  37. 37.
    Ternant D, Berkane Z, Picon L, Gouilleux-Gruart V, Colombel JF, Allez M, 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;54:551–62. doi: 10.1007/s40262-014-0225-3.CrossRefPubMedGoogle Scholar
  38. 38.
    Gisleskog PO, Karlsson MO, Beal SL. Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn. 2002;29:473–505. doi: 10.1023/A:1022972420004.CrossRefPubMedGoogle Scholar
  39. 39.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2009). Ellicott City: Icon Development Solutions; 2009.Google Scholar
  40. 40.
    Lallemand C, Kavrochorianou N, Steenholdt C, Bendtzen K, Ainsworth MA, Meritet J-F, et al. Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFα antagonists. J Immunol Methods. 2011;373:229–39. doi: 10.1016/j.jim.2011.08.022.CrossRefPubMedGoogle Scholar
  41. 41.
    Wang SL, Ohrmund L, Hauenstein S, Salbato J, Reddy R, Monk P, et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods. 2012;382:177–88. doi: 10.1016/j.jim.2012.06.002.CrossRefPubMedGoogle Scholar
  42. 42.
    Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Ainsworth MA. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn’s disease: post hoc analysis of a randomized controlled trial. Am J Gastroenterol. 2014;109:1055–64. doi: 10.1038/ajg.2014.106.CrossRefPubMedGoogle Scholar
  43. 43.
    Edlund H, Melin J, Parra-Guillen ZP, Kloft C. Pharmacokinetics and pharmacokinetic—pharmacodynamic relationships of monoclonal antibodies in children. Clin Pharmacokinet. 2015;54:35–80. doi: 10.1007/s40262-014-0208-4.CrossRefPubMedGoogle Scholar
  44. 44.
    Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008;35:401–21. doi: 10.1007/s10928-008-9094-4.CrossRefPubMedGoogle Scholar
  45. 45.
    Bergstrand M, Karlsson MO. Handling data below the limit of quantification in mixed effect models. AAPS J. 2009;11:371–80. doi: 10.1208/s12248-009-9112-5.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Holford N. The Visual predictive check—superiority to standard diagnostic (Rorschach) plots. PAGE 14 2005 Abstr 738. www.page-meeting.org/?abstract=738.
  47. 47.
    Keizer RJ, Karlsson MO, Hooker A. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT Pharmacometrics Syst Pharmacol. 2013;2:e50. doi: 10.1038/psp.2013.24.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    R Core Team. A language and environment for statistical computing. Vienna, Austria; 2015. http://www.r-project.org/.
  49. 49.
    Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.CrossRefGoogle Scholar
  50. 50.
    Wählby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci. 2002;4:68–79. doi: 10.1208/ps040427.CrossRefPubMedCentralGoogle Scholar
  51. 51.
    Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72:1947–55. doi: 10.1136/annrheumdis-2012-202220.CrossRefPubMedGoogle Scholar
  52. 52.
    Ben-Horin S, Yavzori M, Katz L, Kopylov U, Picard O, Fudim E, et al. The immunogenic part of infliximab is the F(ab′)2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut. 2011;60:41–8. doi: 10.1136/gut.2009.201533.CrossRefPubMedGoogle Scholar
  53. 53.
    Reinisch W, Colombel JF, Sandborn WJ, Mantzaris GJ, Kornbluth A, Adedokun OJ, et al. Factors associated with short- and long-term outcomes of therapy for Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13:539–47. doi: 10.1016/j.cgh.2014.09.031.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhou L, Hoofring SA, Wu Y, Vu T, Ma P, Swanson SJ, et al. Stratification of antibody-positive subjects by antibody level reveals an impact of immunogenicity on pharmacokinetics. AAPS J. 2012;15:30–40. doi: 10.1208/s12248-012-9408-8.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Vande Casteele N, Khanna R, Levesque BG, Stitt L, Zou GY, Singh S, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut. 2014. doi: 10.1136/gutjnl-2014-307883.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Levesque BG, Greenberg GR, Zou G, Sandborn WJ, Singh S, Hauenstein S, et al. A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn’s disease. Aliment Pharmacol Ther. 2014;39:1126–35. doi: 10.1111/apt.12733.CrossRefPubMedGoogle Scholar
  57. 57.
    Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Ainsworth MA. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. 2011;46:310–8. doi: 10.3109/00365521.2010.536254.CrossRefPubMedGoogle Scholar
  58. 58.
    Feuerstein JD, Cullen G, Cheifetz AS. Immune-mediated reactions to anti-tumor necrosis factors in inflammatory bowel disease. Inflamm Bowel Dis. 2015;21:1176–86. doi: 10.1097/MIB.0000000000000279.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Helena Edlund
    • 1
    • 2
    • 3
  • Casper Steenholdt
    • 3
  • Mark A. Ainsworth
    • 3
  • Eva Goebgen
    • 1
  • Jørn Brynskov
    • 3
  • Ole Ø. Thomsen
    • 3
  • Wilhelm Huisinga
    • 4
  • Charlotte Kloft
    • 1
  1. 1.Department of Clinical Pharmacy and Biochemistry, Institute of PharmacyFreie Universitaet BerlinBerlinGermany
  2. 2.Graduate Research Training Program PharMetrXBerlinGermany
  3. 3.Department of GastroenterologyHerlev HospitalHerlevDenmark
  4. 4.Institute of MathematicsUniversitaet PotsdamPotsdamGermany

Personalised recommendations