Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032 ).
However, only low-quality evidence supports this and other guideline recommendations, wrote Joseph D. Feuerstein, MD , of Beth Israel Deaconness Medical Center in Boston and his associates from the AGA Clinical Guidelines Committee. For example, the only randomized controlled trial ( Gut. 2014 Jun;63:919-27) on reactive therapeutic drug monitoring (TDM) of an anti-TNF agent set the target trough concentration for infliximab at 0.5 mcg/mL or more, 10-fold lower than what current evidence supports. The trial found no significant difference between 12-week rates of remission in the TDM and empiric dose escalation arms. “Data supporting these cutoffs were [even] less robust for adalimumab than for infliximab,” according to the guideline. Observational studies suffered from imprecision and flawed designs, and none addressed TDM in clinically remitted patients with active endoscopic disease. “As treatment paradigms shift toward targeting mucosal healing, indirect evidence suggests that using reactive TDM in this situation would be reasonable,” the authors wrote. “However, optimal target trough concentrations for achieving mucosal healing are uncertain and may be higher than those suggested for achieving clinical remission.”
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.