The New Gastroenterologist

The 'Nuts and Bolts' of Drug Concentration Monitoring in IBD

Publish date: March 1, 2017
By
Konstantinos Papamichael, MD, PhD
Adam S. Cheifetz, MD

 

Introduction

Anti–tumor necrosis factor (anti-TNF) therapy is the cornerstone of inflammatory bowel disease (IBD) treatment.1 Nevertheless, up to 30% of patients show no clinical benefit, considered as primary non-responders, while another 50% lose response over time and need to escalate or discontinue anti-TNF therapy due to either pharmacokinetic (PK) or pharmacodynamic issues.2 Therapeutic drug monitoring (TDM), defined as the assessment of drug concentration and anti-drug antibodies (ADA), is emerging as a new therapeutic strategy to better explain, manage, and hopefully prevent these undesired clinical outcomes.3 Moreover, numerous studies have shown that higher serum anti-TNF drug concentrations both during maintenance and induction therapy are associated with favorable objective therapeutic outcomes, suggesting of a ‘treat-to-trough’ in addition to a ‘treat-to-target’ therapeutic approach.4-6 This concept of TDM is not new in IBD. TDM has also been used for optimizing thiopurines.7 This brief review will discuss a practical approach to the use of TDM in IBD with a focus on its use with anti-TNF therapies.

Dr. Konstantinos Papamichael, gastroenterologist in Boston

Dr. Konstantinos Papamichael

Reactive TDM of anti-TNF therapy

Reactive TDM more rationally guides therapeutic decisions for dealing with loss of response to anti-TNF therapy in IBD and is actually more cost-effective.8,9 Patients with sub-therapeutic or undetectable drug concentrations without ADA derive more benefit from dose escalation (increasing the dose or decreasing the interval) compared to those switched to another anti-TNF agent. On the other hand, patients with therapeutic or supra-therapeutic drug concentrations have better outcomes when changing to a medication with a different mechanism of action (as their disease is probably no longer TNF-driven).3 A recent study showed that trough concentration of adalimumab >4.5 mcg/mL or infliximab >3.8 mcg/mL at time of loss of response identifies patients who benefit more from alternative therapies rather than dose escalation or switching to another anti-TNF agent.10 In clinical practice, in order to fully optimize the original anti-TNF, we will typically dose optimize patients to drug concentrations of infliximab and adalimumab to >10 mcg/mL before giving up and changing medications. Moreover, patients with high ADA titer have better outcomes when switched to another anti-TNF rather than undergo further dose escalation.3 Vande Casteele et al, showed that antibodies to infliximab (ATI) >9.1 U/mL at time of loss of response resulted in a likelihood ratio of 3.6 for an unsuccessful intervention, defined as the need to initiate corticosteroids, immunomodulators (IMM), or other medications or infliximab discontinuation within two infusions after the intervention (shorten of infusion intervals, dose increase to 10 mg/kg, or a combination of both).11 A proposed treatment algorithm for using reactive TDM for anti-TNF therapy is shown in Figure 1.

Proactive TDM of anti-TNF therapy

Adam S. Cheifetz, MD

Adam S. Cheifetz, MD

Proactive TDM with drug titration to a target concentration applied in patients with clinical response or remission also appears to improve the efficacy and cost-effectiveness of anti-TNF therapy.12,13 An observational study from our center was the first to demonstrate a significantly greater durability on infliximab in IBD patients in clinical remission who underwent proactive TDM and dose optimization to a therapeutic trough concentration of 5 to 10 mcg/mL when compared to patients receiving standard-of-care and empiric dose escalation and/or reactive TDM.12 Furthermore, this study showed that among patients who achieved an infliximab concentration of ≥5 mcg/mL, there was no difference in infliximab duration between patients on monotherapy and those on combination therapy with an IMM, suggesting that IMM withdrawal can be considered in patients in clinical remission with adequate drug concentration on combination therapy.12 Optimized monotherapy and proactive dose optimization (>5 mcg/mL) with infliximab should also be considered from the outset in patients who do not want to be on a concomitant IMM. Though there is no specific data published to date, we treat adalimumab similarly with dose optimization to concentration >5-10 mcg/mL. Subsequently, the landmark TAXIT trial showed that patients who undergo proactive TDM to the therapeutic drug window of 3-7 mcg/mL need less rescue therapy and more often have detectable infliximab concentrations compared to the clinically based dosing group.13 Moreover, this trial showed that during the initial optimization phase dose escalation in patients with Crohn’s disease (with a suboptimal infliximab concentration) significantly increased the number of patients in clinical remission with a concomitant decrease in C-reactive protein levels.13 A proposed treatment algorithm for using proactive TDM for anti-TNF therapy is shown in Figure 2. Preliminary data also shows that higher drug concentrations early after induction phase (at week fourteen for infliximab, week four for adalimumab and week 8 for certolizumab pegol) are associated with short- and long-term favorable therapeutic outcomes.4,5,14-20 These suggest the utility of an early optimization of anti-TNF therapy even during induction therapy in IBD. Although clinically relevant drug thresholds may vary based on the therapeutic outcome of interest, we typically aim for concentrations > 7 mcg/mL at week four for adalimumab and week fourteen for infliximab. These patients with active inflammation clear drug more quickly (predisposing them to subtherapeutic drug concentrations), and therefore likely derive the most benefit from proactive TDM. Additionally, preliminary data show that proactive TDM may also be useful in other clinical scenarios including better guiding therapeutic decisions towards de-escalation or even discontinuation of anti-TNF in patients achieving clinical remission, or following re-introduction of anti-TNF therapy after a drug holiday.21, 22

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