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There are several clinical scenarios in which therapeutic drug monitoring (TDM) may be beneficial, as determination of the cause of clinical loss of response is critical to treatment optimization.

Loss of response to biologic therapy is a common problem that is likely multifactorial and may be due to antibody development, alterations in drug clearance, or the influence of non-tumour necrosis factor- α (TNF-α)-driven inflammatory processes.(1) TDM, by identifying subtherapeutic drug levels and/or the presence of antidrug antibodies (ADA), can greatly assist in distinguishing between these situations and thus provide useful direction for treatment optimization.(2) Furthermore, low drug levels will in themselves lead to ADA formation.

Drug levels generally correlate with clinical disease activity, and an infliximab trough level greater than or equal to 4 μg/mL is considered to be the cut-off level that will sustain a clinical response.(3) Decreases below this level are associated with secondary loss of response. The reasons for the decreased trough levels are many and include under dosing due to weight gain, increased drug elimination due to inflammation or low serum albumin, and the formation of ADAs.

Following the identification of a low trough level, treatment must be individualized. The patient who is under dosed or has increased drug elimination, and thus a low trough drug level with no ADA, may simply require additional drug to maintain response.(4) In contrast, the patient with a low or high trough level and high ADAs is not likely to respond to additional drug and thus may require alternative measures, including addition of a corticosteroid or immunosuppressant or switching to an alternative therapeutic agent.(5)

TDM can also identify transient ADAs, which do not always lead to permanent loss of response.(6) Assessment has found that patients who have low infliximab trough levels at week 14 have an increased risk of ADA formation and infliximab discontinuation, but low ADA levels (<9.1 U/mL) may be transient and overcome with dose intensification. Follow-up of both trough and ADA levels can identify whether ADA levels decrease and infliximab levels increase, signalling the potential for a regained response.

With subtherapeutic drug levels, intensification of therapy can restore response. The presence of ADAs indicates that a switch to another TNF-α antagonist would be beneficial.(2,7) The presence of high drug levels could indicate a non-TNF-α-driven inflammatory process that requires alternative treatment.

References

1. Souto Rodriguez R, Swoger JM, Barreiro-De Acosta M, Regueiro M. Maximizing the effect of biologics in inflammatory bowel disease. Minerva Gastroenter Dietol. 2012;58(2):101–22.
2. 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.
3. Marits P, Landucci L, Sundin U, et al. Trough s-infliximab and antibodies towards infliximab in a cohort of 79 IBD patients with maintenance infliximab treatment. J Crohns Colitis. 2014;8(8):881–9.
4. Rutgeerts P, Vermeire S, Van Assche G. Predicting the response to infliximab from trough serum levels. Gut. 2010;59(1):7–8.
5. Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(4):444–7.
6. 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.
7. Nielsen OH, Bjerrum JT, Seidelin JB, Nyberg C, Ainsworth M. Biological treatment of Crohn’s disease. Dig Dis. 2012;30(Suppl 3):121–133.

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