The New Gastroenterologist

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

Publish date: March 1, 2017

 

TDM of thiopurines

Measurement of thiopurine metabolites in IBD is typically used in a reactive setting, when lack/loss of response or a drug-related adverse event (leukopenia or abnormal transaminase) occurs.7 However, TDM can be also utilized more proactively to confirm drug adherence and closely monitor patients, especially those with intermediate thiopurine methyltransferase (TPMT) activity or on allopurinol combination therapy.7 Less commonly, proactive dose optimization to a threshold of 6-Thioguanine nucleotide (6-TGN) levels > 230-250 pmol/8x108 red blood cells is performed.23 Nevertheless, the utility of proactive TDM for optimizing thiopurine therapy in IBD clinical practice has not yet been proven, as a clearly defined and clinically validated therapeutic window for thiopurine metabolites remains still largely unknown.24,25 Recent data shows that a 6-TGN level of >125 pmol/8x108 red blood cells is associated with higher infliximab concentration and less ATI formation, suggesting patients on combination therapy may not need “therapeutic” 6-TGN levels to be effective.26

Anti-TNF TDM assays

Several methods are now available for evaluating concentrations of anti-TNF agents and ADA including the enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), homogeneous mobility shift assay (HMSA), and the electro-chemiluminescence immunoassay (ECLIA), but none of them can be considered the gold standard.3 The selection of assay is typically based on cost, local availability, and physician’s preference. Recent data suggests that drug concentrations are generally comparable among the assays currently used, although the detection and quantification of ADA remains challenging depending largely on the analytical properties of the assay used.3, 27 The HMSA, for example, is a drug-tolerant assay (can detect ADA in the presence of drug), while first-generation ELISAs are drug-sensitive assays and when drug is on board ADA cannot be detected (or reported).3 Moreover, there is also lack of data for a clinically relevant low or high ADA titer with each assay. Consequently, standardization and clinical validation of ADA assays for comparison of results across studies is certainly needed.28 It is critically important to understand the assay utilized as mistakes can be made when antibodies are read out in units that make them appear to be high titer and clinically significant when, in fact, they are not.

Conclusions

A growing body of evidence demonstrates the clinical utility of TDM of anti-TNF therapy in IBD clinical practice and a move towards personalized medicine, as it is now clear that “one dose does not fit all patients.” Nevertheless, before a TDM-based approach can be widely implemented and emerge as the new standard-of-care for anti-TNF therapy in IBD, several barriers regarding cost issues (insurance coverage and out of pocket expenses), time lag from serum sampling to test results (typically 5 to 10 days), proper interpretation and application of the results, type of assay used, and the optimal timing of serum collection should be overcome. Initiatives are already underway including the development of accurate, easily accessible, and affordable rapid assays that will allow anti-TNF concentration measurement at the point-of-care site and software-decision support tools or ‘dashboards’ that will incorporate a predictive PK model based on patient and disease characteristics.29,30 Additionally, more data from well-designed prospective studies and randomized controlled trials regarding both induction and maintenance treatment and for all available biologics (originators and biosimilars) are urgently needed. A panel consisting of members of the Building Research in Inflammatory Bowel Disease Globally research alliance (www.BRIDGeIBD.com), and recognized leaders in the field of TDM in IBD has recently published recommendations that help clinicians on the appropriate timing and best way to interpret and respond to TDM results depending on the specific clinical scenario.31

Funding: KP received a fellowship grant from the Hellenic Group for the study of IBD.

Potential competing interests: K.P.: nothing to disclose; A.S.C: received consultancy fees from AbbVie, Janssen, UCB, Takeda, Prometheus, and Pfizer.

Dr. Papamichail is a research fellow and Dr. Cheifetz is the director of the Center for Inflammatory Bowel Diseases, division of gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston. Dr. Papamichail received a fellowship grant from the Hellenic Group for the study of IBD. Dr. Cheifetz received consultancy fees from AbbVie, Janssen, UCB, Takeda, Prometheus, and Pfizer.

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