Richard N. Fedorak, MD
Volume 1 | Issue 10
Using drug levels as a predictor of response requires a validated pharmacokinetic model.(1) Existing models, however, only predict infliximab pharmacokinetics for populations, not for individuals. Models to predict individual pharmacokinetics still require a more precise understanding of factors affecting tumour necrosis factor-α (TNF-α) inhibitor pharmacokinetics.
Therapeutic drug monitoring remains indicated at the time of loss of response. It is not yet clinically indicated as standard of care to predict response to TNF-α inhibitor therapy. Its use as a predictor of response should be limited, at the current time, to research protocols.
Four research studies relating to predicting therapeutic response from drug levels are available:
Pariente B, et al. Inflamm Bowel Dis. 2012
A retrospective study assessed the value of measuring trough and antidrug antibody (ADA) levels for infliximab in inflammatory bowel disease in patients with loss of response as a predictor of future response.(2). No difference in trough levels was seen at the time of loss of response between patients who did or did not respond to dose intensification. More than half of patients with detectable ADAs who received dose intensification experienced both clinical response and decrease or disappearance of ADA levels, which were measured 4 to 12 weeks after dose intensification. All patients who responded to dose intensification had maintained response at 6 months, with the majority in remission.
Paul S, et al. Inflamm Bowel Dis. 2013
A study evaluating therapeutic drug monitoring (TDM) in the prediction of mucosal healing in patients with Crohn’s disease (CD) or ulcerative colitis (UC) after loss of response and infliximab dose intensification measured trough levels, ADAs, C-reactive protein (CRP) levels, and fecal calprotectin before optimization and at week 8.(3) After infliximab dose intensification, half of CD and UC patients achieved mucosal healing. Two factors were independently associated with clinical remission: low infliximab levels (<0.2 μg/mL) at loss of response and an increase in infliximab levels of >0.5 μg/mL. Quartiles of Δ infliximab levels increased in parallel with rates of mucosal healing, with median Δ infliximab levels higher in patients who achieved mucosal healing than in those who did not (2.2 vs 0.2 μg/mL). The optimal cut-off for Δ infliximab level to predict mucosal healing was 0.5 μg/mL. This study found TDM was a strong predictor of mucosal healing after infliximab dose intensification in both CD and UC.
Van Assche G, et al. Gastroenterology. 2008
An open-label randomized trial compared continuation and discontinuation of concomitant immunomodulator therapy at 6 months in patients with CD in remission who were receiving scheduled infliximab therapy.(4) The study measured trough and ADA levels before each infusion. A similar proportion of patients required dose intensification or discontinued infliximab. Infliximab trough levels were lower in the discontinuation group and correlated with higher CRP levels. ADAs were found infrequently, including in patients with multiple low trough infliximab levels. The study concluded that continuation of immunomodulator therapy for more than 6 months has no clear benefit compared with infliximab monotherapy. This study remains to be replicated.
Yanai H, et al. Clin Gastroenterol Hepatol. 2015
An analysis of the association between trough drug levels and ADAs evaluated outcomes of interventions implemented in patients with loss of response to infliximab or adalimumab.(5) Patients with undetectable or low ADA titres responded to dose intensification. Patients with adequate trough levels (>4.5 μg/mL adalimumab and >3.8 μg/mL infliximab) did not respond to dose intensification or a switch to another TNF-α antagonist but did respond to expectant management or out-of-class interventions. Patients with >4 μg/mL-equivalent adalimumab ADA or >9 μg/mL-eq infliximab ADA did not respond to an increased drug dosage but did respond to switching tumour necrosis factor-α antagonists. Measurement of trough and ADA levels can help guide management in more than two-thirds of cases of loss of response, although in remaining patients, these levels do not correlate with specific decision-making recommendations.
Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…