Review article: determination of the therapeutic range for therapeutic drug monitoring of adalimumab and infliximab in patients with inflammatory bowel disease

Abstract

Background Clinical application of therapeutic drug monitoring (TDM) to optimise anti‐TNF therapies in patients with IBD depends upon target ranges. Aims To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab. Methods A systematic review was performed, and relevant literature was summarised and critically examined. Results Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area‐under‐receiver‐operator‐curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end‐points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8‐5.7 µg/mL are reported depending upon end‐points used, with consistent AUROC 0.68‐0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9‐11.8 µg/mL (AUROC 0.66‐0.83) in some studies, but no cut‐off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design. Conclusions Evidence for exposure‐response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.

Therapeutic Monitoring of Adalimumab at Non-Trough Levels to Gauge Its Efficacy in Patients with Inflammatory Bowel Disease in Clinical Practice

“…A previous study on trough level of ADA during maintenance therapy reported that 5-5.8 and 4.9-7.1 µg/mL were the lower limits of the therapeutic range when clinical remission and mucosal healing were the desired targets, respectively; both limits are approximately 4 µg/mL lower than our non-trough level. As these are the lower limits of the therapeutic range and the variation in the levels over 2 weeks between successive ADA administrations is approximately 3 µg/mL [16], our results are valid.…”

“…Interestingly, Ward et al reported that the trough level could be estimated from serum ADA level from days 3 to 9 after ADA injection, suggesting the feasibility of TDM even without trough level measurement of ADA [15]. In addition, authors reported that 8 weeks after the initiation of ADA therapy, the average uctuation in ADA level during the 2 weeks between successive administrations of ADA was approximately 3 µg/mL [16]. Therefore, the purpose of our study was to analyze the effects of serum ADA levels, including its nontrough levels, and AAA presence on subsequent treatment outcomes in patients with IBD receiving ADA.…”

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure

“…This was not influenced by changes in albumin, CRP, BMI or concomitant thiopurine. The effect of a 4‐5 µg/mL increase in levels is unknown, but is unlikely to be associated with adverse effects 20 . While the direction of change seems similar, the more than two‐fold greater increase in maternal infliximab levels found in the previous study compared with that in the current cohort may have reflected the lower numbers of observations in the earlier report.…”

Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease

“…As the therapeutic threshold for IFX is not well defined, we included simulations of PK targets of 3-5 mg/mL. [25][26][27] This study Table 3. Pharmacokinetic (PK) model simulations of attainment of PK targets of trough infliximab (IFX) concentrations of >3 mg/mL, >4 mg/mL, or >5 mg/mL for anti-IFX antibody negative (ADA-) or positive (ADAþ) patients in case of safety pausing IFX therapy in the entire third trimester of pregnancy (IFX-stop); continuation of steady IFX maintenance therapy in the third trimester of pregnancy (IFX cont.…”