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

AAPS Journal

Volumn 19, Issue 1, 2017, Pages 223-233

  Edlund, Helena ^a,b,c   Steenholdt, Casper ^c   Ainsworth, Mark A ^c   Goebgen, Eva ^a   Brynskov, Jørn ^c   Thomsen, Ole Ø ^c   Huisinga, Wilhelm ^d   Kloft, Charlotte ^a  

^a FREIE UNIVERSITÄT BERLIN   (Germany)

^b Graduate Research Training program PharMetrX   (Germany)

^c GENTOFTE UNIVERSITY HOSPITAL   (Denmark)

^d UNIVERSITY OF POTSDAM   (Germany)

Author keywords

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

Indexed keywords

ANTIBODY; INFLIXIMAB; GASTROINTESTINAL AGENT; TUMOR NECROSIS FACTOR;

ADULT; ARTICLE; CENTRAL VOLUME OF DISTRIBUTION; CONTROLLED STUDY; CROHN DISEASE; DRUG BLOOD LEVEL; DRUG CLEARANCE; FEMALE; HUMAN; INTER COMPARTMENTAL CLEARANCE; MAINTENANCE THERAPY; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; OBJECTIVE FUNCTION VALUE; PERIPHERAL VOLUME OF DISTRIBUTION; PHARMACOKINETIC PARAMETERS; SINGLE BLIND PROCEDURE; TREATMENT FAILURE; BIOLOGICAL MODEL; BLOOD; CLINICAL TRIAL (TOPIC); IMMUNOLOGY; METABOLIC CLEARANCE RATE; MIDDLE AGED; YOUNG ADULT;

ADULT; ANTIBODIES; CLINICAL TRIALS AS TOPIC; CROHN DISEASE; FEMALE; GASTROINTESTINAL AGENTS; HUMANS; INFLIXIMAB; MALE; METABOLIC CLEARANCE RATE; MIDDLE AGED; MODELS, BIOLOGICAL; TUMOR NECROSIS FACTOR-ALPHA; YOUNG ADULT;

EID: 84991073419     PISSN: None     EISSN: 15507416     Source Type: Journal    
DOI: 10.1208/s12248-016-9989-8     Document Type: Article

References (58)

1. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59. doi:10.2165/11535960-000000000-0000.
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.
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.
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.
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.
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.
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.
8. De Groot AS, Scott DW. Immunogenicity of protein therapeutics. Trends Immunol. 2007;28:482–90. doi:10.1016/j.it.2007.07.011.
9. Niebecker R, Kloft C. Safety of therapeutic monoclonal antibodies. Curr Drug Saf. 2010;5:275–86. doi:10.2174/157488610792246055.
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.
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.
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.
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. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. 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.
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.
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.
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.
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.
36. Gobburu JV. Pharmacometrics 2020. J Clin Pharmacol. 2010;50:151S–7. doi:10.1177/009127001037697.
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.
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.
39. Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2009). Ellicott City: Icon Development Solutions; 2009.
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.
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.
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.
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.
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.
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.
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. 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.
48. R Core Team. A language and environment for statistical computing. Vienna, Austria; 2015. http://www.r-project.org/.
49. Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.
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.
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.
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.
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.
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.
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.
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.
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.
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.