Review Article

Determination of the Therapeutic Range for Therapeutic Drug Monitoring of Adalimumab and Infliximab in Patients With Inflammatory Bowel Disease

David J. Gibson; Mark G. Ward; Clarissa Rentsch; Antony B. Friedman; Kirstin M. Taylor; Miles P. Sparrow; Peter R. Gibson

Disclosures

Aliment Pharmacol Ther. 2020;51(6):612-628. 

In This Article

Abstract and Introduction

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.

Introduction

Anti-tumour necrosis factor alpha (TNF) therapies are effective for induction and maintenance of remission for ulcerative colitis (UC)[1] and Crohn's disease (CD).[2] However, one-third of patients will have a primary non-response to anti-TNF therapy,[3] while secondary loss of response during maintenance therapy occurs in roughly 20%-40% of those who have an initial response.[4–6] Underlying reasons for loss of response include sub-optimal drug levels related to increased drug clearance that often involves formation of antibodies to the drug, and inflammation driven by non-TNF-dependent pathways. There is a large body of literature for therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD), but the majority of data are either retrospective or based on post hoc analysis of drug registration trials. This has led to recent American Gastroenterology Association (AGA) guidelines stating the available evidence for TDM in IBD to be of low quality.[7] Interestingly, recent British Society of Gastroenterology (BSG) guidelines[8] advocate use of TDM and management changes based on therapeutic or sub-therapeutic drug levels, without actually defining what those levels should be. There are no current European Crohn's Colitis Organisation (ECCO) guidelines to help guide clinicians, further highlighting some of the ambiguity in this field.

One of the key issues in the application of any TDM approach is to define the range of concentrations to which dosing is aimed (ie the therapeutic range). There are clear principles for the calculation of this, but, unfortunately, its determination can be challenging. If clinicians using TDM understand the principles and practicalities around how the therapeutic range for anti-TNF therapies has been defined, there will be a better understanding of how to use it and, at times, why it might change. Thus, the current review will outline the principles and process that have been followed to define the ranges for infliximab and adalimumab, whilst also comparing the performance of the available data for exposure-response relationship (ERR) for the two drugs. Given the paucity of reliable data on golimumab, we have not included any analysis in this review.

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