Role of Therapeutic Drug Monitoring of Biologics in the Treatment of IBD

IBD Clinical Pearl: August 2020 

Konstantinos Papamichael, PhD, MD and Adam S. Cheifetz, MD

Beth Israel Deaconess Medical Center, Boston, Massachusetts

Biological therapies have revolutionized the treatment of moderate to severe Crohn’s disease and ulcerative colitis. Unfortunately, not all patients respond to induction therapy, and many others lose response over time. Therapeutic drug monitoring (TDM) helps to explain these undesirable outcomes, which can be attributed to either low drug concentrations [with or without the development of anti-drug antibodies (ADA)] or a mechanistic failure in patients with adequate drug concentrations [1]. Numerous studies demonstrate an association between higher biologic drug concentrations during both induction and maintenance therapy and favorable therapeutic outcomes in inflammatory bowel diseases (IBD) including clinical and endoscopic remission [2]. These studies include both adult and pediatric populations and typically show that higher concentrations are associated with more stringent outcomes. The prospective study PANTS (personalised anti-TNF therapy in Crohn's disease) showed that post-induction infliximab concentrations >7 mg/L and adalimumab concentrations > 12 mg/L are associated with remission at both week 14 and week 54 [3]. Though most of the data relates to anti-tumor necrosis factor (anti-TNF) therapies, all therapies have positive exposure-outcome relationships [1]. 

Reactive TDM is defined as the evaluation of drug concentration and ADA levels in the setting of primary non-response (PNR) or secondary loss of response (SLR) to a biologic agent. Reactive TDM has rationalized the management of these unwanted clinical outcomes [1, 2]. It can stratify patients with subtherapeutic drug concentrations who will respond to dose escalation from those patients who already have adequate drug exposure and would benefit from a change to a medication with a different mechanism of action suggesting a mechanistic failure. In practice, we do not abandon infliximab or adalimumab unless drug concentrations are > 10-15 μg/ml. Moreover, reactive TDM can identify patients with high ADA levels (defined as 10 U/ml for the homogeneous mobility shift assay and 200 ng/ml, for the second-generation enzyme-linked immunosorbent assay) who would benefit from a switch to another biologic.  If possible, a switch to a therapy within the same class makes the most sense, however this should be done with the addition of an immunomodulator (IMM), such as thiopurines or methotrexate, particularly with anti-TNF. The other option is to switch to a medication outside class. In addition to better directing care, reactive TDM is more cost-effective when compared to empiric infliximab dose optimization [1, 2]. Though the data for reactive TDM for newer biologics is only theoretical at this time, based on exposure-response studies, it makes sense. A panel consisting of members of the Building Research in Inflammatory Bowel Disease Globally research alliance (www.BRIDGeIBD.com) has recently published recommendations that help clinicians on the appropriate timing and best way to interpret and respond to TDM results in specific clinical scenarios [2]. 

Proactive TDM is defined as the evaluation of trough concentration and ADA levels with the goal of optimizing biological therapy to achieve a threshold drug concentration and improve outcomes. The goal of proactive TDM is to improve response rates and prevent PNR and SLR by targeting drug concentrations which are considered to be in the optimal therapeutic range [1, 2]. Data suggest that proactive TDM is associated with better therapeutic outcomes when compared to empiric dose optimization and/or reactive TDM of anti-TNF therapy in IBD [1, 2]. Recently, the PAILOT (Paediatric Crohn’s disease Adalimumab-Level-based Optimisation Treatment) randomized controlled trial (RCT) showed that the steroid-free clinical remission rate at week 72 was higher in children randomized to proactive TDM compared to the group that had reactive TDM [4]. Furthermore, the proactive TDM group had a higher rate of composite (corticosteroid-free clinical remission, C-reactive protein ≤ 0.5 mg/dL and fecal calprotectin ≤ 150 mg/g) remission throughout week 8 to 72 when compared to those who had reactive TDM [4]. Proactive TDM could potentially be utilized to avoid the necessity for combination therapy with an IMM, which can increase the risk for serious and opportunistic infections as well as lymphoma. Two recent observational studies demonstrate that proactive TDM-based infliximab monotherapy is as effective as infliximab combination therapy with an IMM [1]. This concept is further supported by a post-hoc analysis of the SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn Disease) RCT, which shows that patients stratified by infliximab concentration quartiles have comparable outcomes regardless of concomitant azathioprine [5]. Finally, proactive TDM can also efficiently guide infliximab de-escalation in patients in remission. In our clinical practice, dose de-escalation is typically performed in patients in stable clinical remission with an infliximab concentration >15 μg/mL. Following dose de-escalation, patients should continue to be followed with proactive TDM to maintain adequate infliximab concentrations and avoid relapse. 

In conclusion, reactive TDM is the more commonly used strategy and recommended in most guidelines, while proactive TDM is emerging as a new therapeutic strategy and recommended by some groups for better optimizing anti-TNF therapy in IBD. However, before there can be a wide implementation of TDM-based algorithms in real-life clinical practice, several knowledge gaps need to be addressed, including when (peak vs. intermediate vs. trough drug concentrations) and how (what are the optimal drug concentrations to target depending on the therapeutic outcome, IBD phenotype, and type of TDM assay used) to apply TDM. Future perspectives to better optimize TDM include the introduction of pharmacokinetic dashboard models and the use of rapid point of care assays.

Conflict of interest: K.P. received a lecture fee from Mitsubishi Tanabe Pharma. A.S.C.: received a consultancy fee from Janssen, Abbvie, Takeda, Pfizer, Samsung, Arena, Bacainn, EMD Serono, Arsanis, Grifols, Prometheus; and research support from Inform Diagnostics.