Perspectives

Is proactive TDM the way to go?

Publish date: February 28, 2022

Dr. Adam S. Cheifetz

Proactive TDM of anti-TNF therapy has been associated with better patient outcomes in both pediatric and adult populations when compared with empiric dose optimization and/or reactive TDM.^2,3 In patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was found to be more effective than treatment without TDM in sustaining disease control without disease worsening.⁴ Proactive TDM has been associated with better patient outcomes, including increased rates of clinical remission in both pediatric and adult populations and decreased rates of IBD-related surgery, hospitalization, serious infusion reactions, and development of ADAs, when compared with reactive TDM or empiric optimization. Preliminary data suggest that proactive TDM can also be used to efficiently guide dose deescalation in patients in remission with drug concentrations markedly above target and to allow for optimization of infliximab monotherapy so that combination therapy can be employed more judiciously (that is, in a patient who developed rapid ADA to a different anti-TNF).¹ This could potentially attenuate the risks associated with long-term immunomodulator use, which include lymphomas and higher rates of serious and opportunistic infections. A recent study using a pharmacokinetic dashboard showed that the majority of patients with IBD will need accelerated dosing by the third infusion to maintain therapeutic infliximab concentrations during induction and maintenance therapy, highlighting the urgent need for widespread adoption of early proactive TDM.⁵ It is likely that proactive TDM is most important early in therapy when patients are most inflamed and have more rapid drug clearance. For this reason, proactive TDM should ideally be used for all patients during the induction phase. It is our practice to continue to follow drug concentrations one or two times per year once a patient has achieved remission. A recent literature review and consensus statement highlights the utility of TDM and what is known at this time.¹

^{Juan Gaertner/Science Photo Library/Getty Images}

Tumor necrosis factor-alpha, molecular model

TDM should be standard of care for patients with IBD. At minimum, reactive TDM has rationalized the management of PNR, is associated with better outcomes, and is more cost effective than empiric dose escalation.^1,2 In this setting, however, many patients have already developed ADAs that cannot be overcome. At present, anti-TNF therapy remains the most effective agent for our sickest patients with IBD. Given the as-yet limited armamentarium of medications available, particularly for patients with fistulizing perianal Crohn’s disease (CD) and severe ulcerative colitis (UC), proactive TDM, which allows for improved optimization and long-term durability of biologics, is essential to the care of any IBD patient requiring these medications. Proactive TDM should ideally be used for all patients during the induction phase and at least once during maintenance therapy. There is also the potential for TDM-driven dose de-escalation for patients in remission and optimization of infliximab monotherapy, thus avoiding combination therapy with an immunomodulator in some cases. Future perspectives for a more precise application of TDM include the use of pharmacokinetic modeling dashboards and pharmacogenetics toward achieving truly individualized medicine.³

Dr. Rabinowitz, Dr. Papamichael, and Dr. Cheifetz are with the department of medicine and division of gastroenterology at Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. Dr. Rabinowitz reports no conflicts of interest. Dr. Papamichael reports lecture fees from Mitsubishi Tanabe Pharma and Physicians’ Education Resource; consultancy fee from Prometheus Laboratories; and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. Dr. Cheifetz reports consulting for Janssen, AbbVie, Samsung, Arena Pharmaceuticals, Grifols, Prometheus, Bristol Myers Squibb, Artizan Biosciences, Artugan Therapeutics, and Equillium.