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Relation between trough drug levels and clinical response

In inflammatory bowel disease, infliximab concentrations correlate with clinical efficacy and treatment outcomes.(1) Multiple studies demonstrate that the presence and level of antidrug antibodies (ADA) to infliximab correlates with loss of clinical efficacy and an increased risk of infusion reactions. Less correlation exists between adalimumab and certolizumab pegol concentrations and outcomes, but as additional data become available, the importance of ADA to adalimumab or certolizumab is becoming more apparent. In general, high drug trough levels are associated with clinical improvement, and low levels are associated with a poor response.

A comparison of infliximab levels with outcomes in moderate-to-severe ulcerative colitis used data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2). Infliximab levels at Weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission.(2) Infliximab levels of 41 μg/mL at 8 weeks and 3.7 μg/mL during maintenance were linked to optimal outcomes

Similarly, a study prospectively evaluating the relation between trough serum infliximab levels and disease activity measured infliximab levels in patients with Crohn’s disease (CD).(3) An infliximab trough level <3 μg/mL at Week 8 was significantly associated with loss of response and a higher CRP level. In addition, patients with ADAs at Week 4 or 8 had a reduced probability of therapeutic infliximab trough levels than those without ADAs.

Factors associated with antidrug antibody development

ADAs develop after exposure to the drug and during a time when drug levels are low. ADAs cannot form in the presence of high drug (i.e. antigen) levels. ADA development results in decreased efficacy, infusion reactions, and delayed hypersensitivity.(1) Patients treated with concomitant immunomodulators or hydrocortisone have a lower incidence of ADAs than patients receiving monotherapy. Relative to immunomodulators, both methotrexate or azathioprine significantly reduced ADA formation, with no difference between the two drugs.(4)

In patients with loss of response, low levels of ADAs may be transient and may not always lead to a need to discontinue therapy, whereas persistent high ADA levels lead to permanent loss of response.(5)

Approach to treatment optimization

When drug levels are low and ADAs are undetectable, dose escalation may be the most successful strategy.(1) The pattern of symptoms can guide the dose intensification approach, with a shorter dosing interval for patients who experience symptoms before the next scheduled dose and a higher dose for patients with a decreased infusion response.

High ADAs indicate that continued treatment is likely to be unsuccessful.(1) Although low ADA levels may be overcome with dose intensification, sustained high ADA levels are associated with permanent loss of response. High ADA levels (>9.1 U/mL) at loss of response have been associated with ADA persistence and unsuccessful dose optimization.(5) Switching to another TNF-α antagonist is the appropriate therapeutic choice in this situation.(1) A poor response to a second TNF-α antagonist would necessitate switching out of class to a non-TNF agent.(6)

Therapeutic drug levels associated with loss of response may indicate an inflammatory process not relying on TNF-α or possibly an alternative etiology for the symptoms.(1) Treatment with a drug with an alternative mechanism of action may be useful for patients with persistent disease on investigation, and an alternative etiology for the symptoms should be sought for patients with inactive disease.

References

1. Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Therap Adv Gastroenterol. 2013;6(4):269–93.
2. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis.Gastroenterology. 2014;([Epub ahead of print])
3. Levesque BG, Greenberg GR, Zou G, 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(10):1126–35.
4. Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56(9):1226–31.
5. 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(6):962–71.
6. Khanna R, Sattin BD, Afif W, et al. Review article: a clinician’s guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38(5):447–59.

Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…