Infliximab, a chimeric anti-TNF antibody, has revolutionized the treatment of the inflammatory bowel diseases (IBD) namely Crohn’s disease (CD) and ulcerative colitis (UC). Nevertheless, up to 30% of patients have a primary non-response (PNR), and most notably, up to 80% do not achieve clinical remission following induction therapy.1 Preliminary data from therapeutic drug monitoring (TDM) studies suggest that these undesired clinical outcomes can be attributed either to low drug concentrations with or without antidrug antibodies or a mechanistic failure.2, 3
In a recent issue of Alimentary Pharmacology and Therapeutics, Bar-Yoseph et al.4, in one of the largest cohorts, evaluated the association of early induction infliximab concentrations and antibodies to infliximab (ATI) with PNR. PNR was defined as the lack of clinical improvement by the end of induction period (week 14), which necessitated cessation of infliximab therapy. They found that both week 2 and week 6 infliximab concentrations were significantly lower among patients with PNR compared to responders. Additionally, ATI positivity at weeks 2 and 6 was also associated with PRN. Most importantly they identified a week 2 infliximab concentration <6.8 μg/mL and ATI titer >4.3 μg/mL-eq predictive of PNR.4 This finding is of great value as the therapeutic drug window to target for infliximab induction therapy is largely unknown. Nevertheless, we think that these infliximab concentrations, although adequate to prevent clinically defined PNR, are probably too low for achieving more stringent therapeutic outcomes, such as early mucosal healing or at least early clinical remission.5–10 The same group using the same in-house developed assay has previously shown that infliximab concentrations >9.2 μg/mL at week 2 were associated with fistula response at week 14.3 However, a large retrospective study from Leuven demonstrated that higher week 2 infliximab concentrations >28.3 μg/mL were associated with early mucosal healing (week 10–14) in UC9. Furthermore, a recent pharmacokinetic (PK) analysis of the prospective randomized controlled trial (RCT) investigating tailored treatment with infliximab for active Crohn’s disease (TAILORIX) showed that infliximab concentrations >23.1 μg/mL at week 2 were related with endoscopic remission at week 12 in CD using the Leuven’s in-house developed enzyme-linked immunosorbent assay.6 This discrepancy, as described also by the authors, may arise from differences in evaluated therapeutic outcomes, the TDM assay used and the IBD phenotype (Table 1). This, along with the fact that induction infliximab concentrations can fluctuate more than maintenance treatment due to PK issues, makes it hard to define clinically relevant infliximab induction concentration thresholds.
Table 1.
Serum infliximab concentration thresholds during induction therapy associated with early therapeutic outcomes in inflammatory bowel disease.
| Time point | IBD type | Therapeutic outcome of interest | Threshold (μg/mL)a | TDM assay | Assay type | Ref. |
|---|---|---|---|---|---|---|
| w2 | CD | Clinical response (w14) | >16.9b | ELISA | Theradiag | [7] |
| w2 | CD | Clinical remission (w14) | >20.4b | ELISA | Theradiag | [7] |
| w2 | CD | Endoscopic remission (w12) | >23.1 | ELISA | In house Leuven | [6] |
| w2 | CD | Fistula response (w14) | >9.2 | ELISA | AHLC | [3] |
| w2 | UC | Clinical response (w14) | >11.5b | ELISA | Theradiag | [7] |
| w2 | UC | Mucosal healing (w10–14) | ≥28.3 | ELISA | In house Leuven | [9] |
| w2 | UC | Clinical remission (w14) | >15.3b | ELISA | Theradiag | [7] |
| w2 | UC | Clinical remission (w30) | >14.5b | ELISA | Theradiag | [7] |
| w2 | UC | Clinical remission (w14) | >21.3 | ELISA | Mitsubishi Tanabe Pharma Corp | [8] |
| w2 | CD/UC | Clinical response (w14) | >6.8 | ELISA | AHLC | [4] |
| w6 | CD | Endoscopic remission (w12) | >10 | ELISA | In house Leuven | [6] |
| w6 | CD | Fistula response (w14) | >7.2 | ELISA | AHLC | [3] |
| w6 | UC | Clinical response (w8) | >22 | ELISA | Janssen Biotech Inc | [5] |
| w6 | UC | Mucosal healing (w10–14) | ≥15 | ELISA | In house Leuven | [9] |
| w6 | UC | Endoscopic response (w8) | >6.6 | ELISA | Sanquin Diagnostics | [2] |
| w6 | CD/UC | Clinical response (w14) | >3.5 | ELISA | AHLC | [4] |
| w6 | CD/UC | ATI formation | <13 | HMSA | Prometheus | [10] |
Based on receiver operating characteristic analysis;
Infliximab biosimilar CT-P13.
ELISA: enzyme-linked immunosorbent assay; HMSA: homogeneous mobility shift assay; AHLC: antihuman lambda chain antibody; CD: Crohn’s disease; UC: ulcerative colitis; TDM: therapeutic drug monitoring; ATI: antibodies to infliximab; w: week; Ref: reference.
In conclusion, this study suggests that PNR of infliximab in IBD can be better explained by PK problems and immunogenicity rather than a mechanistic failure and that unfortunately anti-TNF are underdosed in many individuals. As new tools are soon to be available, such as point of care devices for measuring infliximab concentrations and PK models for accurately calculating infliximab dosing, early utilization of TDM to optimize anti-TNF therapy is not far away. Nevertheless, before a TDM-based therapeutic strategy during induction therapy can be widely applied data from RCTs is certainly warranted.
ACKNOWLEDGEMENTS
Declaration of personal interests: K.P.: nothing to disclose; A.S.C: received consultancy fees from AbbVie, Janssen, UCB, Takeda, Prometheus, and Pfizer.
Funding information:
“Ruth L. Kirschstein NRSA Institutional Research Training Grant (5T32DK007760–18)”.
Footnotes
Declaration of funding interests: None
References
- 1.Papamichael K, Casteele NV, Ferrante M, et al. Therapeutic drug monitoring during induction of anti-tumor necrosis factor therapy in inflammatory bowel disease: defining a therapeutic drug window. Inflamm Bowel Dis 2017;23:1510–5. [DOI] [PubMed] [Google Scholar]
- 2.Brandse JF, Mathot RA, van der Kleij D, et al. Pharmacokinetic features and presence of anti-drug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2016;14:251–8. [DOI] [PubMed] [Google Scholar]
- 3.Davidov Y, Ungar B, Bar-Yoseph H, et al. Association of induction infliximab levels with clinical response in perianal Crohn’s disease. J Crohns Colitis 2017;11:549–555 [DOI] [PubMed] [Google Scholar]
- 4.Bar-Yoseph H, Levhar N, Selinger L, et al. Early drug and anti-infliximab antibody levels for prediction of primary nonresponse to infliximab therapy. Aliment Pharmacol Ther 2018; 47:212–218 [DOI] [PubMed] [Google Scholar]
- 5.Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology 2014;147:1296–307.e5. [DOI] [PubMed] [Google Scholar]
- 6.Dreesen E, D’Haens G, Baert F, et al. Infliximab exposure predicts superior endoscopic outcomes in patients with active Crohn’s disease: pharmacokinetic–pharmacodynamic analysis of TAILORIX. J Crohns Colitis 2018. 12 (suppl 1) S063–S064 [Google Scholar]
- 7.Gonczi L, Vegh Z, Golovics PA, et al. Prediction of short- and medium-term efficacy of biosimilar infliximab therapy. Do trough levels and antidrug antibody levels or clinical and biochemical markers play the more important role? J Crohns Colitis 2017;11:697–705 [DOI] [PubMed] [Google Scholar]
- 8.Kobayashi T, Suzuki Y, Motoya S, et al. First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis-results from a multicenter prospective randomized controlled trial and its post hoc analysis. J Gastroenterol 2016;51:241–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Papamichael K, Van Stappen T, Vande Casteele N, et al. Infliximab concentration thresholds during induction therapy are associated with short-term mucosal healing in patients with ulcerative colitis. Clin Gastroenterol Hepatol 2016;14:543–9. [DOI] [PubMed] [Google Scholar]
- 10.Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol 2013;108:962–71. [DOI] [PubMed] [Google Scholar]