When in relation to the TNF-α antagonist’s dose should I perform TDM?

When in relation to the TNF-α antagonist’s dose should I perform TDM?

Peter L. Lakatos, MD

Volume 1 | Issue 6

Runs 1:13

TDM at trough

Substantial data exist regarding the measurement of tumour necrosis factor-α (TNF-α) levels at trough (that is, immediately before dosing), although in many studies, trough drug levels were measured for reasons other than loss of response.

A study evaluating markers associated with outcomes with infliximab therapy to assist in individualizing decision-making in patients with refractory ulcerative colitis (UC) used regression analysis.(1) Independent factors predicting relapse-free and colectomy-free survival included trough infliximab levels ≥2.5 μg/mL measured at week 14. Determination of trough infliximab levels at week 14 may therefore be useful in guiding therapy.

An infliximab reinitiation study measured trough levels and antidrug antibodies (ADAs) before the second or third and the fourth infusion for patients receiving an induction regimen, and before the second and third infusions for patients not receiving an induction regimen.(2) Short-term response was associated with reinitiation with concomitant immunomodulator therapy and absent ADAs at the first measurement. Long-term response was associated with previous discontinuation due to pregnancy or remission and higher trough levels at the first measurement time point. Also at this time point, undetectable ADAs were associated with absence of infusion reactions. Therefore, TDM trough levels before the second infusion in patients in whom infliximab is reinitiated may provide prognostic information.

A study of infliximab trough and ADA levels as predictors of sustained response in patients with CD measured trough levels after induction therapy, at weeks 14 or 22.(3) The study found that trough levels >3 μg/mL were associated with a decreased risk of treatment failure and a sustained treatment response. The presence of ADAs and the need for corticosteroid therapy increased the risk of treatment failure. Although patients receiving concomitant immunomodulator therapy had higher infliximab trough levels than those not receiving combination therapy (5.51 vs. 0.71 μg/mL), in this study concomitant immunomodulator therapy did not affect the risk of treatment failure.  Therefore, TDM trough infixiamb levels >3 μg/mL at week 14 may predict long-term success.

A post hoc analysis of A Crohn’s disease Clinical study Evaluating infliximab in a New long term Treatment regimen (ACCENT I) compared week 14 infliximab trough levels and the percentage decrease in CRP from baseline to week 14 in patients with and without a durable sustained response through week 54.(4) The study found that the optimal predictor of a durable sustained response to an infliximab dose of 5 mg/kg was a week 14 trough level ≥3.5 mg/mL. This trough level was not a predictor of durable sustained response in patients receiving infliximab 10 mg/kg. Significantly higher early median serum infliximab trough levels were seen in patients with durable sustained response to 5 mg/kg who also received a concomitant immunomodulator than in patients who eventually lost response. In addition, a decrease of ≥60% in CRP in patients with an elevated baseline CRP (>8.0 mg/L) was an optimal predictor. Therefore, measuring infliximab trough levels at week 14 may provide not only a prediction of the likelihood of achieving a durable sustained response but also a guide to dose optimization in patients with low trough levels. 

To date, the measurement of infliximab trough levels in clinical care should be limited to loss of response or adverse events. However, measurement of trough levels at specified intervals of time may, in the future, provide important prognostic information.

TDM at alternative time points

Accurate prediction of individual drug levels throughout treatment requires a validated pharmacokinetic model.(5) Existing models, however, predict pharmacokinetics of infliximab only for populations, not for individuals. Elaboration of a model to predict individual pharmacokinetics requires more precise definition of factors affecting drug pharmacokinetics, using a large number of samples from a substantial cohort. Generally, trough drug levels are measured, although some data exist on samples taken 4 weeks after dosing. A recent report also indicates that patients with loss of response have lower drug levels immediately after an infusion than do patients with a maintained response.

As an example, a study prospectively evaluating the relation between trough serum infliximab levels and disease activity measured infliximab levels in patients with Crohn’s disease (CD) who had received at least 5 consecutive infliximab infusions. The study assessed the Crohn’s Disease Activity Index (CDAI), serum infliximab, CRP levels and ADAs at Weeks 0, 4 and 8.(6) Infliximab infusions were given at Weeks 0 and 8. Changes in mean CDAI score between infusions mirrored changes in mean CRP levels. An infliximab trough level <3 μg/mL at Week 8 was significantly associated with an increase in CDAI score of ≥70 points between infusions and with a greater likelihood of CRP >5 mg/L at Week 8. Patients with ADAs at Weeks 4 or 8 had a reduced probability of therapeutic infliximab trough levels than those without ADAs.

The clinical utility of approaches other than trough levels has not been evaluated, and considerably less data exist about the measurement of drug levels at alternative time points.

References

  1. Arias MT, Vande Casteele N, Vermeire S, et al. A panel to predict long-term outcome of infliximab therapy for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2014; [Epub ahead of print].
  2. Baert F, Drobne D, Gils A, et al. Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy. Clin Gastroenterol Hepatol. 2014;12(9):1474–81.e2; quiz e91.
  3. Bortlik M, Duricova D, Malickova K, et al. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease. J Crohns Colitis. 2013;7(9):736–43.
  4. Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of c-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial.Gut. 2014;63(11):1721–7.
  5. 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.
  6. 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.

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

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