Magnitude of Increased Infliximab Clearance Imposed by Anti-infliximab Antibodies in Crohn’s Disease Is Determined by Their Concentration
- 459 Downloads
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 WORDSanti-drug antibodies Crohn’s disease frequentist’s prior model infliximab population pharmacokinetic modeling
- Anti-IFX Abs (+/−)
Anti-infliximab antibodies (positive/negative)
Inflammatory bowel disease
Homogenous mobility shift assay
- (>/<) LLOQ
(Above/below) lower limit of quantification
Reporter gene assay
Tumor necrosis factor α
The authors would like to thank Eurodiagnostica (Malmö, Sweden) and Prometheus Laboratories Inc. (San Diego, CA, USA).
- 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.
- 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
- 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.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.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.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.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
- 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.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
- 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.
- 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
- 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
- 39.Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2009). Ellicott City: Icon Development Solutions; 2009.Google Scholar
- 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.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.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
- 46.Holford N. The Visual predictive check—superiority to standard diagnostic (Rorschach) plots. PAGE 14 2005 Abstr 738. www.page-meeting.org/?abstract=738.
- 48.R Core Team. A language and environment for statistical computing. Vienna, Austria; 2015. http://www.r-project.org/.
- 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