Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease: A Nationwide Survey of Anti-TNF Therapy Practices, Attitudes, and Barriers

Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR). To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX. Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing. Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing. Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped.

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This study evaluated the long-term effectiveness and safety of a multidisciplinary early proactive therapeutic drug monitoring (TDM) program combined with Bayesian forecasting for infliximab (IFX) dose adjustment in a real-world dataset of paediatric patients with inflammatory bowel disease (IBD). A descriptive, ambispective, single-centre study of paediatric patients with IBD who underwent IFX serum concentration measurements between September 2015 and September 2023. The patients received reactive TDM before September 2019 (n = 17) and proactive TDM thereafter (n = 21). We analysed for clinical, biological, and endoscopic remission; treatment failure; hospitalisations; emergency visits; and adverse drug reactions. The IFX doses were adjusted to maintain trough concentrations ≥ 5 µg/mL, with specific targets for proactive TDM. Of the 38 patients, 21 had Crohn's disease (CD), 16 ulcerative colitis (UC), and 1 undetermined IBD. The mean (standard deviation) IFX trough concentrations were 6.83 (5.66) µg/mL (reactive) and 12.38 (9.24) µg/mL (proactive) (p = 0.08). No statistically significant differences between groups were found in remission rates or treatment failure. The proactive group had fewer hospitalisations (14.29% vs. 23.53%; p = 0.47) and shorter median hospitalisation days (6 vs. 19; p = 0.50), although the difference was not statistically significant. The number of patients with adverse reactions (infusion related reactions and infections) was higher in the proactive group (38.10% vs. 23.53%; p = 0.34) but the difference was not significantly different. Proactive TDM showed no significant differences in treatment outcomes compared to reactive TDM. However, the results in both the reactive and proactive TDM groups were not worse than those reported in other studies. Further studies with larger samples are needed to optimize the treatment strategies for pediatric IBD patients.

ObjectiveTo address the efficacy and safety of proactive therapeutic drug monitoring of biologic drugs for patients with inflammatory bowel disease, inflammatory arthritis, and psoriasis.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, Central,...

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Background: Up to a third of inflammatory bowel disease) patients show primary nonresponse to antitumor necrosis factor (anti-TNF) biological therapy, and of those who respond, up to 40% develop secondary loss of response (LOR). Therapeutic drug monitoring (TDM) plays a crucial role in assessing patients with LOR to guide therapy by giving more of the drug or switching to a different biological agent. Although reactive TDM is suggested or recommended by the majority of gastroenterology associations, proactive TDM seems to be more controversial. Summary: In this article, we discuss the updated guidelines on TDM and will also discuss the available data supporting proactive and reactive TDM in patients with Crohn’s disease and those with ulcerative colitis using the different available biological agents. Key Messages: Therapeutic drug monitoring (TDM) is a valuable tool to aid in inflammatory bowel disease (IBD) therapy optimization. Reactive TDM is widely accepted in IBD patients with suspected loss of response, especially in those receiving antitumor necrosis factor (anti-TNF) agents. Proactive TDM is emerging as a reasonable approach to patients initiated on anti-TNF therapy, specifically infliximab and, to some extent, adalimumab, particularly for patients with severe ulcerative colitis and fistulizing Crohn’s disease. Similarly, TDM may play a role in patients considering de-escalation from combination therapy. To date, proactive TDM is not widely applied to ustekinumab and vedolizumab and more data are required before this becomes part of clinical practice.

BackgroundPrimary non-response (PNR) and secondary loss of response (LoR) to anti-TNF therapy are a significant challenge in up to 45% of patients with IBD. Therapeutic drug monitoring (TDM) refers to...

Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non-response and secondary loss of response and has shown to be more cost-effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta-analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model-based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model-based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C-reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real-life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.

It Is Time to Treat to Trough: Staying Ahead of the Curve in Biologic Testing

INTRODUCTION: A growing body of evidence supports use of therapeutic drug monitoring (TDM) in improving efficacy and cost-effectiveness of anti-TNF therapy in patients with inflammatory bowel disease (IBD). Existing and evolving knowledge of TDM in clinical practice is less well understood. Our objective was to assess attitudes and barriers to TDM use with anti-TNF's in the UK. METHODS: A 17-question survey was distributed to members of the British Society of Gastroenterology. Information on clinician characteristics, demographics, use and barriers towards implementing TDM with anti-TNF's was collected. Logistic regression was used to predict factors influencing TDM use. RESULTS: 243 respondents participated (51.6% male) of which 237 respondents met inclusion criteria; treating >5 IBD patients and at least 1 with an anti-TNF per month. Of the total respondents, 45% were Consultant Gastroenterologists (GI), 40% IBD Nurse Specialists (CNS) and 15% GI Specialist Registrars (SPR). Of these 237 respondents, TDM was used by 95.7% for secondary loss of response; 71.4% for primary non-response and 53.6% used TDM proactively. Barriers for TDM use were time lag in receiving results (27.1%), lack of awareness of guidelines (15.6%), and cost (11.9%). Clinicians working at a teaching hospital were more likely to use TDM compared to a district hospital (OR 2.6, 95% CI 0.71-9.8). IBD CNS and GI SPR used TDM more often, when compared to Consultant GI (OR 2.6, 95% CI 0.69-10 & OR 1.5, 95% CI 0.3-7.2 respectively). Clinicians practising for >20 years were more likely to check TDM than less experienced clinicians (OR 4.1, 95% CI 0.4-41.8). Clinicians with large volume IBD practice (>50% IBD patients per month) were more likely to check TDM than those seeing fewer IBD patients (OR 45.6, 95% CI 7.5-275). Proactive TDM was more likely to be used by clinicians working in a tertiary care setting (OR 2.25, 95% CI 0.84-6.05), IBD CNS (OR 1.2, 95% CI 0.6-2.1), clinicians managing large volume IBD practice (OR 10.8, 95% CI 1.2-90) and clinicians with 5-9 years of experience in practice (OR 2.6 & CI 1.04-6.42). CONCLUSION: Significant barriers to TDM implementation in the UK are time lag from test to result, lack of awareness of current guidelines and evolving knowledge, cost and less experience. Validation of point of care testing, lower cost assays, and wider dissemination of current evolving paradigms with updated recommendations may further optimise treatment with anti-TNF therapies.

Background and aims Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. Methods A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. Results In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01–0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. Conclusion TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.

This review focuses on recent advancements in anti-TNF therapeutic drug monitoring (TDM), pharmacogenetics and personalized drug selection for children with inflammatory bowel disease (IBD). Several real-world studies and one clinical trial in children have demonstrated that proactive TDM, targeting higher exposure concentrations (> 5µg/mL), can improve disease remission rates and enhance durability of the anti-TNF biologics. Recent data from both adult and pediatric IBD patients have revealed an association between a genetic polymorphism (HLA-DQA1*05) and the development of auto-drug antibodies. The impact of this association on clinical outcomes, considering more routine use proactive TDM and dose optimization in children, is still under investigation. Additionally, recent studies have identified potential inflammatory signatures and biomarkers that may serve as companion diagnostics for anti-TNF biologics. The effective management of anti-TNF therapies in children with IBD requires evidence-based precision dosing strategies, including routine TDM and proactive pharmacodynamic assessments.

This systematic review and meta-analysis aimed to determine whether the use of therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients on anti-tumour necrosis factor (anti-TNF) therapy results in improved rates of clinical and endoscopic remission, surgery, corticosteroid-free remission and hospitalisation. MEDLINE, EMBASE, EMBASE classic, PubMed, Cochrane central databases register of controlled trials and Cochrane Specialised Trials Register were searched between 01 Janurary 1946 and 08 April 2022. Randomised controlled trials (RCTs) and prospective and retrospective observational studies were included, comparing TDM to standard of care (SOC) or reactive vs proactive TDM. Results were reported as pooled relative risks (RR) with 95% confidence intervals (95% CI). Twenty-six studies, including 9 RCTs, were included. Compared to SOC, proactive TDM was associated with a significantly decreased risk of treatment failure (RR 0.64, 95% CI 0.48-0.85 p<0.01), and a non-significant decrease in need for surgery (RR 0.51, 95% CI 0.25-1.02) and hospitalisation (RR 0.64, 95% CI 0.40-1.00). Furthermore compared to SOC, Proactive TDM was associated with higher rates of endoscopic remission (RR 1.19, 95% CI 0.93-1.53) and clinical remission (RR 1.07, 95% CI 0.97-1.18). Compared to reactive TDM, proactive TDM was associated with significant decreased risk of treatment failure (RR 0.46, 95% CI 0.21 = 0.98, p = 0.04) and significant reduction in hospitalisation (RR 0.33, 95% CI 0.21-0.54, p < 0.01). Compared to SOC, proactive TDM was associated with significant benefit in reducing treatment failure. Compared to reactive TDM, proactive TDM led to a significant reduction in hospitalisation and treatment failure. More studies with larger RCTs and standardised assays are needed to substantiate these results and validate the cost-effectiveness of TDM.

Introduction The use of therapeutic drug monitoring (TDM) for infliximab and adalimumab in the treatment of inflammatory bowel disease (IBD) is becoming increasingly commonplace. In cases of non-response (primary or secondary) TDM can provide a clearer understanding of the cause of treatment failure and offer a rationale for steps taken to recapture response. However, several factors regarding its use remain uncertain such as minimum therapeutic thresholds, the relevance of antidrug antibodies found in the presence of detectable drug, and the benefits of TDM during remission. Methods We designed a survey that included 5 TDM-based clinical scenarios, for which the ‘most appropriate’ responses were based on the Building Research in IBD Globally (BRIDGe) groups ‘Anti-TNF Optimizer’ (http://www.bridgeibd.com/anti-tnf-optimizer). This resource combines available TDM evidence with expert consensus. A link to our online survey tool was sent to various IBD clinician groups in June 2017 including members of the British Society of Gastroenterology, Royal College of Nursing IBD Network and the gastroenterology special interest group of the UK Clinical Pharmacy Association. Results We received 142 responses. Of these, 110 (77%) were complete, comprising 50 (45%) consultants, 30 (27%) trainees, 25 (23%) IBD nurse specialists and 5 (5%) gastroenterology pharmacists, and were used for analysis. Over half (61, 55%) only carry out TDM in non-response. The remainder use TDM routinely, during stable maintenance therapy for patients in remission. Only 15 (14%) respondents reported being clear and confident in their understanding of the difference between drug-sensitive and drug-tolerant assays. Moreover, most (82, 75%) were unsure as to which type their laboratory uses. Lower therapeutic thresholds used by clinicians were variable (figure 1). Consultants, high-frequency TDM users (>3 requests/month) and clinicians with larger anti-TNF cohorts (>100 patients) were significantly more likely to select the ‘most appropriate’ answer to at least 1 of the 5 TDM scenarios (figure 2). Conclusions These results demonstrate marked heterogeneity in the practical use, understanding and interpretation of biologic TDM in IBD. Biologic decision-making, informed by TDM, should involve consultation with experienced clinicians who are frequent TDM users, ideally, as part of a multidisciplinary, biologics-focused IBD meeting.

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.