Remo Panaccione, MD
Volume 1 | Issue 3
Different therapeutic drug monitoring (TDM) assays have varying characteristics. The most commonly used method is an enzyme-linked immunosorbent assay (ELISA). The ELISA in common use, a double-antigen assay, cannot measure antidrug antibodies (ADAs) in the presence of drug, as the drug competes with the detection antigen. Therefore, this assay is only useful when trough levels are undetectable. A comparison of three different ELISAs found good correlation of infliximab and ADA measurement among the assays, although some false positive infliximab trough levels were seen.(1) An alternative ELISA, using antihuman lambda chain (AHLC) antibody for ADA detection may be able to overcome interference of infliximab with ADA measurement.(2) The simultaneous presence of both drug and ADAs may be a marker for evolving loss of response.
Fluid-phase radioimmunoassay (RIA) complexes infliximab with radiolabelled antigen and estimates infliximab concentration by measuring the radioactivity of the complex. This technique can also measure ADAs to infliximab, although high concentrations can interfere with detection. In a study of patients receiving maintenance infliximab, RIA has shown good correlation with clinical parameters.(3)
The newest and most promising type of assay is the high-pressure liquid chromatography-based homogeneous mobility shift assay (HMSA). HMSA dissociates drug-ADA complexes, and hence can quantify drug and ADAs independently. This method has been validated against the standard ELISA.(4) ADA titres and drug levels were highly correlated, and HMSA also identified false-positive ADA results from ELISA.
A retrospective cohort study found that patients with Crohn’s disease who lost response had undetectable infliximab levels and median ADA levels of 35 U/mL, whereas those who maintained response had median infliximab levels of 2.8 μg/mL and undetectable ADA levels.(3) The infliximab cut-off value associated with loss of response was <0.5 μg/mL. Similarly, the cut-off value for ADAs was >10 U/mL. Combining measurements of infliximab and ADA levels further increased accuracy in predicting loss of response. Similar results were seen in patients with ulcerative colitis.
Another study of patients receiving maintenance infliximab treatment found mean serum infliximab levels to be significantly higher in patients in remission (4.1 μg/mL) than in patients with a disease flare (1.8 μg/mL). This correlation suggests that higher drug levels provide better disease control or that increased disease activity accelerates drug clearance.(5) Although infliximab levels did not differ between patients receiving concomitant immunosuppression and those on monotherapy, the occurrence of ADAs was significantly lower in patients receiving immunosuppression.
A retrospective study of pediatric and adult patients with inflammatory bowel disease (IBD) and secondary loss of response to tumour necrosis factor-α (TNF-α) antagonists evaluated the correlation between infliximab or adalimumab levels, ADA titres, and responses to different therapeutic interventions.(6) Patients with adequate trough levels, identified as >4.5 μg/mL adalimumab or >3.8 μg/mL infliximab, failed to respond to either an increase in drug dosage or a switch to another TNF-α antagonist. However, they were likely to respond to an out-of-class switch. Increased titres of ADA identified patients who did not respond to an increased drug dosage but did respond when switched to another TNF-α antagonist. Dosage increases were more effective for patients with no or low titres of ADAs. The findings of this study suggest that trough levels of drug and ADA titres can guide therapeutic decisions for patients with IBD and secondary loss of response to TNF-α antagonist therapy.
Overall, the accuracy of both trough drug levels and levels of ADA achievable today appears to be adequate to guide clinical decision-making in patients with IBD.
Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…