Therapeutic drug monitoring – a bright future for biological IBD therapy

Graham Johnson, Managing Director at BIOHIT Ltd

Crohn’s disease (CD) and ulcerative colitis (UC) are two of the most frequently diagnosed inflammatory bowel conditions, affecting about 0.81 % of adults in the UK.¹ Although both disorders are characterised by chronic inflammation and result in similar symptoms – mainly lower abdomen pain and swelling, diarrhoea, weight loss and fatigue – UC affects the large intestine, while CD can impact any part of the digestive tract.² Treatments for these conditions typically target the chronic inflammation, but some advanced therapies – such as monoclonal antibody biologicals – also run the risk of inducing a humoral immune response. In this blog, we discuss how therapeutic drug monitoring (TDM) allows clinicians to gain a clear understanding of IBD progression and drug response to optimise patient outcomes.

Treating inflammatory bowel disease

The management of IBD usually involves multiple approaches, including medical treatment and changes to lifestyle factors, such as diet, exercise and stress management. The aim of most medicinal treatments is to reduce the inflammation that triggers the signs and symptoms of the disease, helping patients to reach and maintain remission.³ Commonly administered therapies include small molecule anti-inflammatory drugs, immunosuppressants, and biomedicines targeting disease-specific inflammatory mediators.^4,5 Biotherapeutics have become increasingly popular in recent years, as they offer high specificity and minimal side effects compared to more generic anti-inflammatories. One particularly popular first-line biologic for the treatment of IBD is infliximab (IFX), a chimeric monoclonal antibody which works by inhibiting the pro-inflammatory cytokine TNF-alpha. TNF-alpha is part of the body’s normal response to infection but, in people with IBD, too much is produced, heightening the body’s inflammatory response and resulting in digestive tract irritation.

The biologics challenge

Biological drugs such as IFX are often effective at reducing inflammatory symptoms in IBD patients, but they also pose a risk of inducing a humoral immune response. Patients’ immune systems may produce anti-drug antibodies (ADAs) in response to these treatments, which bind to and inhibit the drug, causing subsequent loss of efficacy. As a result, almost 50 % of biologics require discontinuation during treatment due to an initial failure to respond to therapy or a loss of response (LOR) over time.⁵ During IBD therapy, primary non-response to an administered biologic could stem from drug interactions, pharmacodynamics, pharmacokinetics or several other factors. A LOR to IFX over time could be due to bioavailability issues or the production of ADAs blocking binding of the drug to the TNF-alpha receptor.

TDM can therefore provide clinicians with a useful tool when managing IBD, allowing the measurement of both circulating drug and ADA levels. However, TDM has its own challenges; knowing how to interpret results is key to successful outcomes, and understanding the role of ADAs in individual patients is particularly important. For example, when a biological drug elicits a humoral response, ADAs will bind to and neutralise the circulating drug, rendering it ineffective and increasing its clearance from the body. This creates a clinical conundrum, as it will not be clear at this point whether the low serum drug level has resulted from ADAs, or an insufficient dosage. Differentiating between these two possible causes for LOR is important.

Monitoring patient responses

Low level ADAs are not always apparent or clinically significant. It is sometimes possible to ‘out-titrate’ the ADAs formed – either by increasing the therapeutic dose or reducing the dosage interval – to reach an optimum drug trough level within the target therapeutic window. However, this may introduce unwanted side effects, and is often seen as a reactive approach. Moreover, TDM strategies incorporating ADA detection can be impaired by difficulties in recognising low-titre ADAs, which are often bound to the circulating drug, and are therefore ‘hidden’ from measurement. ‘Drug-sensitive’ assays measuring freely circulating ADAs may therefore lack the discriminatory power to detect immunogenicity in some cases.

More recently, pre-emptive TDM strategies have been explored to help predict the course of a patient’s response to treatment and overcome the challenges of ADA assay sensitivity. In this scenario, ‘drug-tolerant’ total ADA assays that can detect low-titre ADAs – even in the presence of circulating drug – are employed. In combination with the serum drug level, this information can be used by clinicians to gain a clearer understanding of an individual’s drug response, highlighting any immunogenicity sooner so that the progression or regression of IBD can be monitored proactively for the duration of treatment.

Measuring free drug and total ADA levels can help clinicians to tailor treatment to the patient; individuals with low drug levels but no antibodies may respond to a higher dosage, while patients with low drug levels and high ADA levels may require supplementary immunomodulators or need to switch to a similar medication in the same class, or to another class of drug entirely. Therefore, in a pre-emptive treatment strategy, TDM provides gastroenterologists with the information they need to continually modify treatment and prevent LOR from occurring.

Collaboration to streamline care

Effective IBD management – and the widespread implementation of TDM – requires resources to be shared and collaborative efforts to be made between healthcare services. Many UK hospitals rely on outsourcing TDM testing for a range of biological therapies to national reference laboratories such as the Exeter Clinical Laboratory (ECL) – part of the Royal Devon University Healthcare NHS Foundation Trust – which uses BIOHIT’s IDKmonitor^® assays to provide efficient assessment of circulating drug levels, and free and total ADAs. This access to accurate and efficient testing, as well as the expert interpretation by clinical scientists, provides treating clinicians with greater insights and confidence about treatment efficacy. Additionally, in cases where patients do not respond as expected, TDM can help to determine whether this results from an insufficient dose of biologic, the patient processing the drug too quickly, or the generation of ADAs that limit therapeutic response. This ensures that clinicians can make informed decisions about modifying patients’ treatment plans, resulting in better optimised, more individually-tailored IBD care.

References

1. New research shows over 1 in 123 people in UK living with Crohn’s or Colitis. 2022. Crohn’s & Colitis UK. Available at: https://crohnsandcolitis.org.uk/news-stories/news-items/new-research-shows-over-1-in-123-people-in-uk-living-with-crohn-s-or-colitis (Accessed: 10 May 2023).
2. Inflammatory bowel disease. NHS. Available at: https://www.nhs.uk/conditions/inflammatory-bowel-disease/ (Accessed: 10 May 2023).
3. Pithadia, A.B. and Jain, S. 2011. Treatment of inflammatory bowel disease (IBD). Pharmacological Reports, 63(3):629-642. doi: 10.1016/s1734-1140(11)70575-8.
4. Biotherapeutics and advanced therapies. 2023. International Federation of Pharmaceutical Manufacturers & Associations. Available at: https://www.ifpma.org/areas-of-work/strengthening-regulatory-systems/biotherapeutics-and-advanced-therapies/ (Accessed: 10 May 2023).
5. Ashat, D. and Long, M.D. 2021. Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease: What, When and Why?. Practical Gastroenterology, 45(7):22-27.