Proactive Therapeutic Drug Monitoring of Adalimumab Is Associated With Better Long-term Outcomes Compared With Standard of Care in Patients With Inflammatory Bowel Disease

Papamichael, Konstantinos; Juncadella, Anna C; Wong, Danny; Rakowsky, Shana; Sattler, Lindsey; Campbell, James P.; Vaughn, Byron P.; Cheifetz, Adam S.

doi:10.1093/ecco-jcc/jjz018

Cited by 115 publications

(85 citation statements)

References 30 publications

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“…97 Although well-designed large prospective studies are lacking, there are preliminary data mainly from retrospective studies that demonstrate that proactive TDM is associated with better therapeutic outcomes compared with empiric dose optimization and/or reactive TDM. 38,39,103,104,128 Furthermore, numerous retrospective studies 23,24,26,29,[31][32][33]67,73,74,[77][78][79]129,130 and some post hoc analyses of RCTs [47][48][49]71,76,94,131,132 have shown that higher biologic drug concentrations are associated with favorable short-term and long-term therapeutic outcomes in IBD (Supplementary Table 1, Tables 1 and 2). There do appear to be certain clinical scenarios that proactive TDM of anti-TNF therapy can efficiently guide therapeutic decisions, such as treatment de-escalation, 133 the application of optimized monotherapy instead of combo therapy with immunomodulator, 82 restarting therapy after a long drug holiday, 27 and treatment cessation on deep remission.…”

Section: Discussionmentioning

confidence: 99%

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Papamichael

Cheifetz

Melmed

et al. 2019

Clinical Gastroenterology and Hepatology

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237

248

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BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 [ strongly disagree and 10 [ strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ‡7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

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Section: Discussionmentioning

confidence: 99%

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Papamichael

Cheifetz

Melmed

et al. 2019

Clinical Gastroenterology and Hepatology

Self Cite

237

248

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“…Hence, upper limits have been estimated from clinical observation of the relationship of incremental efficacy with incremental dosing. Papamichael et al divided 382 patients (311 with CD) into quartiles according to the adalimumab levels (Q1: <5.6 µg/mL; Q2: 5.6‐12 µg/mL; Q3: 12‐17.8 µg/mL; Q4: >17.8 µg/mL). Using a proactive TDM strategy, the authors observed higher rates of treatment failure in quartiles 1‐2 (between 56% and 58%) compared to quartiles 3‐4 (between 19% and 23%), suggesting that no additional efficacy was achieved above 17.8 µg/mL.…”

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

confidence: 99%

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

Aliment Pharmacol Ther

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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.

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“…Cost savings may also enable earlier access to biologics in some countries [145,146]. If cost savings were directed toward additional services, therapeutic drug monitoring (TDM) could help optimize TNF inhibitor therapy and deliver personalized care for patients with IBD [147,148]. TDM involves measurement of drug and ADA levels: ADA formation is frequently associated with reduced primary efficacy and loss of response to IBD treatment [50] and may be predicted by factors including drug clearance and body weight [149].…”

Section: Pharmacoeconomists' Perspective: Cost Of and Access To Biolomentioning

confidence: 99%

The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases

Kim

Alten

Avedano³

et al. 2020

Drugs

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Biologics have transformed the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Biosimilars-biologic medicines with no clinically meaningful differences in safety or efficacy from licensed originators-can stimulate market competition and have the potential to expand patient access to biologics within the parameters of treatment recommendations. However, maximizing the benefits of biosimilars requires cooperation between multiple stakeholders. Regulators and developers should collaborate to ensure biosimilars reach patients rapidly without compromising stringent quality, safety, or efficacy standards. Pharmacoeconomic evaluations and payer policies should be updated following biosimilar market entry, minimizing the risk of imposing nonmedical barriers to biologic treatment. In RA, disparities between treatment guidelines and national reimbursement criteria could be addressed to ensure more uniform patient access to biologics and enable rheumatologists to effectively implement treat-to-target strategies. In IBD, the cost-effectiveness of biologic treatment earlier in the disease course is likely to improve when biosimilars are incorporated into pharmacoeconomic analyses. Patient understanding of biosimilars is crucial for treatment success and avoiding nocebo effects. Full understanding of biosimilars by physicians and carefully considered communication strategies can help support patients initiating or switching to biosimilars. Developers must operate efficiently to be sustainable, without undermining product quality, the reliability of the supply chain, or pharmacovigilance. Developers should also facilitate information sharing to meet the needs of other stakeholders. Such collaboration will help to ensure a sustainable future for both the biosimilar market and healthcare systems, supporting the availability of effective treatments for patients.

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Proactive Therapeutic Drug Monitoring of Adalimumab Is Associated With Better Long-term Outcomes Compared With Standard of Care in Patients With Inflammatory Bowel Disease

Cited by 115 publications

References 30 publications

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

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

The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases

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