Speaker: Jo LW Lambert

Therapeutic drug monitoring (TDM) could be a useful approach in managing a 42-year-old overweight female patient with a good Psoriasis Area and Severity Index score on Secukinumab but who is experiencing recurrent fungal infections. Instead of immediately switching to another biological, adjusting the current treatment dose based on clinical response might be a viable option. In a multicentre trial, patients with low disease activity are randomized, with one group undergoing a 50% dose reduction, while the other group is on a standard dose. The study, in collaboration with several universities, is investigating whether this reduction leads to more disease flares or maintains stability. The results, including secondary endpoints on drug concentrations in the blood and their predictive value for dose adjustments, are expected in 2025. 

TDM allows for personalized dosing by measuring drug levels in the blood. For patients with high levels, the dosing interval could be extended (e.g., from every 8 weeks to every 10 or more), while patients with low levels may require dose increases. This approach not only helps in managing the patient’s disease but also has the potential to reduce safety issues and healthcare costs. TDM involves three main steps. Firstly, a blood sample collection is performed, with an important prerequisite being that the process is convenient and patient-friendly. Next, serum drug levels are detected using tests that are consistent, sensitive, and specific. Finally, there is the interpretation of the drug level in relation to the target concentration, with a prerequisite of a reliable relationship between drug exposure and clinical response.

Data from fields like rheumatology and gastroenterology, where TDM was explored earlier, are available. For example, in the TAILORIX trial involving infliximab, the dose was adjusted based on serum drug concentration. However, it didn’t lead to better clinical outcomes or corticosteroid-free remission. A critical review reveals a methodological issue—the cut-off value for serum drug concentration was set too low (3 µg/mL), which may have been insufficient to correlate with a good clinical response. In another study, the TAXIT trial compared clinically guided dose adjustments to TDM-based dosing. Although concentration-based dosing didn’t show superiority, fewer flares were observed when guided by TDM. Similarly, the NOR-DRUM B trial used proactive monitoring of infliximab levels in several immune-mediated diseases, including psoriasis. Proactive TDM helped maintain better disease control without worsening symptoms, indicating its potential effectiveness in sustaining clinical results. In the case of Hidradenitis Suppurativa (HS), research has looked at adalimumab levels, drawing parallels with ulcerative colitis. However, transposing findings from one condition to another is problematic, as each disease requires a specific therapeutic drug window. In HS, patients with suboptimal responses to adalimumab were found to have subtherapeutic serum levels, suggesting potential underdosing. The London group has implemented a TDM-based dosing scheme for adalimumab in clinical practice, using serum levels measured at week 4 and week 16. This approach provides a rational framework for adjusting doses, switching agents, or fine-tuning treatment, making decision-making more pragmatic. 

There has been growing interest in utilizing TDM for newer biologics, particularly in the treatment of psoriasis. A research team is preparing to conduct a randomized controlled trial comparing proactive TDM with standard care for these biologics. One of the primary challenges they aim to address is determining the optimal target concentration for each biologic in psoriasis treatment. Over the past six to seven years, significant progress has been made, with target concentrations for many biologics now published, though ongoing work continues for newer agents such as Risankizumab, Tildrakizumab, and Brodalumab. The upcoming Helios trial will focus on three biologics: Secukinumab, Ixekizumab, and Guselkumab. In the trial, patients will have their blood drug levels measured, and based on these results, clinicians will either recommend dose reductions if the levels are above the target concentration or dose increases if they are below the threshold. The hypothesis of the trial is that proactive TDM will be non-inferior to standard care in maintaining disease control while also offering better safety outcomes. Additionally, it is expected to lead to an approximate 9% reduction in healthcare costs, which is a key economic incentive for government support.

Despite the potential benefits, there are still practical challenges associated with TDM in clinical practice. Blood collection ideally needs to occur at trough levels just before the next injection, which can limit the window for testing. Furthermore, the tests themselves can show variability. For instance, adalimumab concentrations tested in different labs might produce slightly different results, making it difficult to determine whether to adjust the dose or not. In some cases, patients may face out-of-pocket costs for these tests, as reimbursement is not always available, and the specificity of the tests remains a concern. These challenges highlight the need for further refinement of TDM protocols before they can become a routine part of biological therapy management. 

The European Commission has initiated an international collaboration called ENOTA (European Network on Optimising Treatment with Therapeutic Antibodies) to enhance treatment strategies for chronic inflammatory diseases using therapeutic antibodies. This initiative focuses on developing guidance for therapeutic drug monitoring (TDM), which is anticipated to play a significant role in future treatment optimization. ENOTA emphasizes model-informed precision dosing (MIPD), which aims to tailor dosing to individual patients by integrating various factors such as serum drug levels, weight, age, and disease duration. This approach seeks to calculate the optimal timing for subsequent doses, making treatment more personalized. Additionally, ENOTA is working to improve TDM capabilities in academic labs and clinical centers throughout Europe, particularly in Belgium and the Netherlands, where advanced testing facilities are available. These facilities plan to utilize innovative technologies, including mass spectrometry in conjunction with enzyme-linked immunosorbent assay, to enhance the reliability of TDM. One significant threat identified is the skepticism surrounding TDM, as many practitioners are hesitant to adopt this approach due to the historical separation of diagnostics and biological treatments. Despite these challenges, there is optimism that TDM can become a standard practice in patient care, provided that robust theoretical and evidence-based data are gathered to support its efficacy.

Future perspectives in TDM emphasize the potential for rapid testing methods, such as lateral flow assays, to enhance clinical practice. Advancements in mass spectrometry are anticipated to improve accuracy and precision in drug measurements without significantly increasing costs. MIPD is expected to contribute significantly to improved treatment outcomes. The establishment of biobanks is becoming increasingly important as research groups compile extensive datasets from biological patients. These biobanks can support large pharmacokinetic and pharmacodynamics modelling efforts, leading to more accurate target concentration determinations and identification of risk factors that may impact treatment responses. The integration of technology into patient care is expected to facilitate the input of patient data into computer systems, allowing healthcare professionals to obtain precise dosing recommendations. The application of artificial intelligence in analysing large datasets may also enhance decision-making processes in clinical settings. However, machine learning will require robust pharmacokinetic and pharmacodynamic models for effective simulations, highlighting the need for larger datasets to support meaningful analysis. 

The potential application of TDM in oral therapies, in addition to biologics, presents significant opportunities for optimization. For medications such as Deucravacitinib and Orismilast, TDM may be useful in identifying patients who are underdosed under the current one-size-fits-all dosing guidelines. A more personalized dosing strategy based on individual drug levels could enhance the sustainability and effectiveness of these new oral therapies. This approach highlights the importance of individualized treatment strategies aimed at optimizing patient outcomes and minimizing the risk of underdosing.

33, European Academy of Dermatology and Venereology Congress, 25-28 September 2024, Amsterdam.