Success and safety of high infliximab trough levels in inflammatory bowel disease

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.

Section: Determination Of the Therapeutic Range For Anti‐tnf Agentsmentioning

confidence: 61%

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

Gibson

Ward

Rentsch

et al. 2020

“…Because of the known mismatch between serum and tissue anti‐TNF levels, especially in patients with active disease, we hypothesize that targeting a higher serum trough level above the 7.0 μg/mL upper limit of the therapeutic window might better neutralize tissue TNF and hence increase mucosal healing rates, especially in patients with a high mucosal IL13RA2 expression. Retrospective data already suggested that higher trough levels are safe and result in better endoscopic outcomes . Similarly, recent prospective data from the UK PANTS study also demonstrated the beneficial impact of higher post‐induction serum levels on 1‐year outcome in anti‐TNF‐treated patients .…”

Section: Discussionmentioning

confidence: 89%

Mucosal IL13RA2 expression predicts nonresponse to anti‐TNF therapy in Crohn's disease

Verstockt

Creyns

et al. 2019

SummaryBackgroundIleocolonic expression of IL13RA2 has been identified as a predictive marker for nonresponsiveness to infliximab (IFX) in patients with Crohn's disease (CD).AimTo validate the IL13RA2 biomarker, study its anti‐TNF specificity and get a better understanding of the underlying biology driving its expression.Methods IL13RA2 mucosal expression was studied in a cohort of adalimumab and vedolizumab treated patients. To identify the upstream regulators of anti‐TNF nonresponsiveness, weighted gene co‐expression network analysis was applied on publicly available microarray data of IFX‐treated patients. Selected serum proteins, including TNF, were measured prior to first IFX exposure and compared between healers and nonhealers.ResultsIncreased mucosal IL13RA2 expression prior to start of biological therapy was predictive for anti‐TNF nonresponsiveness specifically (AUROC, area under the curve = 0.90, P < 0.001 in anti‐TNF vs AUROC = 0.63, P = 0.30 in vedolizumab treated patients). In baseline biopsies, TNF‐driven pathways were significantly enriched in future anti‐TNF nonhealers (P = 5.0 × 10−34). We found an increased baseline mucosal TNF burden in nonhealers (P = 0.02), and TNF mRNA correlated significantly with IL13RA2 expression (ρ = 0.55, P = 0.02). Baseline serum TNF levels were significantly lower in nonhealers (P = 0.04), and correlated inversely with IFX serum induction levels (r = −0.45, P = 0.002 at week 6).ConclusionsIncreased mucosal IL13RA2 expression is associated with an increased mucosal TNF burden in CD patients. In view of its specificity for prediction of anti‐TNF therapy resistance, mucosal IL13RA2 expression is a potential biomarker for therapy selection and/or for the need of increased anti‐TNF drug dosing.

“…These patients typically have low infliximab trough levels, suggesting a pharmacokinetic issue . Conversely, high trough levels have been associated with clinical and biochemical remission, C‐reactive protein and faecal calprotectin normalisation, mucosal healing and even fistula healing . Consequently, different strategies have been developed to tackle low trough levels, such as adding azathioprine to infliximab during the most vulnerable period of 6‐12 months after its initiation, a strategy known as combination treatment .…”

Section: Introductionmentioning

confidence: 99%

“…By improving pharmacokinetics, azathioprine co‐treatment increases infliximab trough levels . Alternatively, trough levels can also be increased by escalating the dose of infliximab or by shortening the interval between infusions of infliximab—a strategy known as “optimised infliximab monotherapy.” The latter may have the advantage of increased safety, as high trough levels were not associated with an increased risk of complications . Conversely, combination treatment has a well‐documented increased risk of infection and malignancy .…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, trough levels can also be increased by escalating the dose of infliximab or by shortening the interval between infusions of infliximab—a strategy known as “optimised infliximab monotherapy.” The latter may have the advantage of increased safety, as high trough levels were not associated with an increased risk of complications . Conversely, combination treatment has a well‐documented increased risk of infection and malignancy . Elevated cost could be a potential shortcoming of optimised infliximab monotherapy due to higher drug consumption because of less favourable pharmacokinetics than the combination treatment.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in inflammatory bowel disease

Drobne

Kurent

Golob

et al. 2019

Self Cite

Background: Combination treatment with azathioprine for 6-12 months is the preferred strategy for starting infliximab due to improved pharmacokinetics. However, optimised infliximab monotherapy with proactive dose escalations in case of low trough levels is a potentially safer but under-studied alternative.Aim: To compare the clinical success and infliximab consumption of combination vs optimised monotherapy strategies.Methods: We studied the clinical success and infliximab consumption with both strategies in 149 patients (94 Crohn's disease; 55 ulcerative colitis) starting infliximab and undergoing intensive drug monitoring assisted treatment optimisation.Results: The drug retention rates were similar for optimised monotherapy and combination treatment after induction (96% vs 97%, P = 0.73), after the first year (90% vs 83%, P = 0.23) and at the end of follow-up (74% vs 75%, P = 0.968). Similarly, no significant differences were observed for steroid use at year 1 (5% vs 14%, P = 0.08) or mucosal healing at the end of follow-up (64% vs 67%, P = 0.8). Higher infliximab consumption (7.6 mg/kg q8 weeks [interquartile range (IQR): 5.9-10.3] vs 6.4 mg/kg q8 weeks [IQR: 5.2-8.0], P = 0.019) combined with lower trough levels (1.7 µg/mL [IQR: 0.3-6.6] vs 5.0 µg/mL [2.5-8.7], P = 0.012) resulted in almost 3-fold higher drug-to-trough ratio (3.9 vs 1.5) in monotherapy compared to combination strategy at year 1. At the end of follow-up, when azathioprine had been discontinued for a median of 14 [IQR: 3-33] months, these differences disappeared. Conclusions:In this study, optimised infliximab monotherapy was as clinically effective as combination therapy, but was associated with significantly higher infliximab consumption. The infliximab-sparing effect disappeared after azathioprine withdrawal.