Loss of response to biologic therapy is a common problem that appears to be multifactorial and related to development of antidrug antibodies (ADAs), alterations in drug clearance, inflammatory processes not driven by tumour necrosis factor-α (TNF-α), and other factors.(1) Therapeutic drug monitoring (TDM) can help to distinguish among these situations, providing useful direction for treatment optimization.(2) 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.(2,3) The presence of high drug levels could indicate a non-TNF-α-driven inflammatory process that requires alternative treatment.
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.(4) Patients with undetectable or low ADA titres responded to dose intensification. Patients with high-titre adalimumab or infliximab ADA did not respond to an increased drug dosage but did respond to switching TNF-α antagonists. Patients with adequate trough levels (>4.5 μg/mL adalimumab or >3.8 μg/mL infliximab) did not respond to dose intensification or a switch to another TNF-α antagonist but did respond to either expectant management or out-of-class interventions. TDM can help to identify the appropriate approach to optimizing treatment in patients with loss of response.
Measuring trough levels and ADAs is becoming increasingly important in the management of loss of response, and the value of TDM and the identification of trough drug cut-off levels associated with efficacy and clinical remission has been demonstrated. Nevertheless, not all studies have consistent results. As a result, TDM does not replace clinical evaluation of the patient, confirmation of active disease using endoscopy, imaging, laboratory investigations, and exclusion of disease complications.(5) In addition, optimal measurement methods and cut-offs have not yet been agreed upon. Several questions also remain, including the clinical relevance of ADAs in patients with detectable trough levels.
Nevertheless, TDM allows more informed clinical decisions in the setting of secondary loss of response to biologic therapy. Less successful strategies, such as empiric dose escalation in the setting of therapeutic drug levels or high-titre ADAs can be avoided, and clinic visits can be reduced. Indeed, an algorithm-based approach to clinical decision-making that uses TDM may be both useful and cost effective. A randomized, controlled, single-blind, multicentre study investigated the cost effectiveness of algorithm-based interventions after loss of response to infliximab in 69 patients with IBD.(6) The algorithm was designed to identify reasons for therapeutic failure, and the study found that using an algorithm based on both trough and ADA levels significantly reduced treatment costs (34% in the intention-to-treat population) compared with empiric dose intensification, without negatively affecting efficacy. A 1-year follow-up study determined that the financial benefit of the algorithm-based approach was maintained.(7)
Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…