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New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 25898

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Special Issue Editor

Dr. Konstantinos Papamichael

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Guest Editor

Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Interests: therapeutic drug monitoring; anti-TNF therapy; biologics; inflammatory bowel disease; immunogenicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Biologics have revolutionized the treatment of inflammatory bowel disease (IBD) and other immune mediated inflammatory diseases (IMID), such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. Nevertheless, some patients show no clinical benefit following induction, and others see a diminished response over time. Both these unwanted outcomes are mostly attributed to inadequate drug concentrations and often the development of antidrug antibodies. Reactive therapeutic drug monitoring (TDM) has rationalized the management of lack or loss of response and is more cost-effective than empirical treatment optimization based only on symptoms. Recent data suggest that proactive TDM and dosing to a therapeutic drug concentration in patients in clinical remission is associated with improved long-term outcomes. However, before a wide implementation of TDM in real life clinical practice, several barriers need to be overcome, one of the most important being the optimal drug concentrations to target that can be outcome-, assay-, and even patient-specific. Other knowledge gaps include the role of peak drug concentrations, stool or tissue drug concentrations, total drug exposure, TDM during induction therapy, and TDM for biologics other than anti-TNFs. Future perspectives regarding the role of TDM include the use of rapid point-of-care assays as well as the incorporation of pharmacokinetic modeling and pharmacogenetics towards individual personalized medicine. The aim of this Special Issue is to highlight recent advances in the use of TDM in IBD and other IMID.

Dr. Konstantinos Papamichael
Guest Editor

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Keywords

Ulcerative colitis
Crohn’s disease
Inflammatory bowel disease
Infliximab
Adalimumab
Certolizumab pegol
Golimumab
Vedolizumab
Ustekinumab
Therapeutic drug monitoring
Immunogenicity
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis

Published Papers (12 papers)

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Research

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11 pages, 1563 KiB

Open AccessArticle

Higher Adalimumab Trough Levels Are Associated with Histologic Remission and Mucosal Healing in Inflammatory Bowel Disease

by Rochelle Wong, Lihui Qin, Yushan Pan, Prerna Mahtani, Randy Longman, Dana Lukin, Ellen Scherl and Robert Battat

J. Clin. Med. 2023, 12(21), 6796; https://doi.org/10.3390/jcm12216796 - 27 Oct 2023

Viewed by 1301

Abstract

(1) Many patients with inflammatory bowel disease (IBD) in endoscopic remission have persistent histologic activity, which is associated with worse outcomes. There are limited data on the association between adalimumab drug concentrations and histologic outcomes using validated histologic indices. We aimed to assess the relationship between adalimumab concentrations and the Robarts Histopathology Index (RHI). (2) Patients from a tertiary IBD center from 2013 to 2020 with serum adalimumab (ADA) trough concentrations measured during maintenance therapy (≥14 weeks) and a colonoscopy or flexible sigmoidoscopy with biopsies performed within 90 days of drug level were included. Blinded histologic scoring using the RHI was performed. Primary analysis assessed the relationship between adalimumab drug concentrations and histologic remission using receiver operating characteristic curve analysis. (3) In 36 patients (26 Crohn’s Disease, 9 ulcerative colitis, 1 indeterminate), median adalimumab concentrations were higher (17.3 ug/mL, 12.2–24.0) in patients with histologic remission compared to those without (10.3 ug/mL, 6.8–13.9, p = 0.008). The optimal ADA concentration identified using the Youden threshold was ≥16.3 ug/mL (sensitivity 70%, specificity 90%). Patients with ADA ≥ 16.3 ug/mL had higher histologic remission rates (78%) compared to lower ADA concentrations (14%, p= 0.002), as well as higher mucosal healing rates (86%) compared to lower levels (12%, p = 0.001). Symptoms correlated weakly and non-significantly with both histologic (RHI) scores (r = 0.25, p = 0.2) and adalimumab concentrations (r = 0.05, p = 0.8). (4) The current study demonstrated that higher serum adalimumab concentrations (≥16.3 ug/mL) are needed for histologic remission and mucosal healing assessed using the RHI. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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10 pages, 843 KiB

Open AccessArticle

Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases

by Christian Primas, Walter Reinisch, John C. Panetta, Alexander Eser, Diane R. Mould and Thierry Dervieux

J. Clin. Med. 2022, 11(12), 3316; https://doi.org/10.3390/jcm11123316 - 9 Jun 2022

Cited by 8 | Viewed by 2101

Abstract

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings’s regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming’s slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7–30.2; OR = 21.0 CI95%: 3.4–127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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15 pages, 3952 KiB

Open AccessArticle

Promising Tools to Facilitate the Implementation of TDM of Biologics in Clinical Practice

by Rani Soenen, Christophe Stove, Alessio Capobianco, Hanne De Schutter, Marie Dobbelaere, Tahmina Mahjor, Merel Follens, Jo Lambert and Lynda Grine

J. Clin. Med. 2022, 11(11), 3011; https://doi.org/10.3390/jcm11113011 - 26 May 2022

Cited by 5 | Viewed by 1994

Abstract

Therapeutic drug monitoring (TDM) of biologics—encompassing the measurement of (trough) concentrations and anti-drug antibodies—is emerging as a valuable tool for clinical decision making. While this strategy needs further validation, attention on its implementation into the clinic is warranted. Rapid testing and easy sampling are key to its implementation. Here, we aimed to evaluate the feasibility and volunteers’ perception of home microsampling for quantification of adalimumab (ADM) concentrations in psoriasis patients. In addition, we compared lateral flow testing (LFT) with enzyme-linked immunosorbent assay (ELISA). Patients participating in the SUPRA-A study (clinicaltrials.gov NCT04028713) were asked to participate in a substudy where volumetric absorptive microsampling (VAMS) was performed at home. At three time points, whole blood and corresponding serum samples were collected for ADM measurement using an in-house ELISA. In addition, the patients’ perspective on microsampling was evaluated via a questionnaire. LFT-obtained ADM concentrations agreed very well with ELISA results (Pearson’s correlation = 0.95 and R² = 0.89). ADM concentrations determined in both capillary (via finger prick) and corresponding venous blood VAMS samples correlated strongly with serum concentrations (Pearson’s correlation = 0.87). Our preliminary data (n = 7) on rapid testing and home-based microsampling are considered promising with regard to TDM implementation for adalimumab, warranting further research. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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Review

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16 pages, 1288 KiB

Open AccessReview

What Should We Know about Drug Levels and Therapeutic Drug Monitoring during Pregnancy and Breastfeeding in Inflammatory Bowel Disease under Biologic Therapy?

by Mathilde Barrau, Xavier Roblin, Leslie Andromaque, Aurore Rozieres, Mathias Faure, Stéphane Paul and Stéphane Nancey

J. Clin. Med. 2023, 12(23), 7495; https://doi.org/10.3390/jcm12237495 - 4 Dec 2023

Viewed by 1084

Abstract

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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11 pages, 769 KiB

Open AccessFeature PaperReview

Drug Clearance in Patients with Inflammatory Bowel Disease Treated with Biologics

by Tina Deyhim, Adam S. Cheifetz and Konstantinos Papamichael

J. Clin. Med. 2023, 12(22), 7132; https://doi.org/10.3390/jcm12227132 - 16 Nov 2023

Cited by 2 | Viewed by 1295

Abstract

Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response, and up to 50% of the patients can experience a loss of response to anti-tumor necrosis factor therapy. These undesirable outcomes can be attributed to either a mechanistic failure or pharmacokinetic (PK) issues characterized by an inadequate drug exposure and a high drug clearance. There are several factors associated with accelerated clearance of biologics including increased body weight, low serum albumin and immunogenicity. Drug clearance has gained a lot of attention recently as cumulative data suggest that there is an association between drug clearance and therapeutic outcomes in patients with IBD. Moreover, clearance is used by model informed precision dosing (MIDP) tools, or PK dashboards, to adjust the dosing for reaching a target drug concentration threshold towards a more personalized application of TDM. However, the role of drug clearance in clinical practice is yet to be determined. This comprehensive review aims to present data regarding the variables affecting the clearance of specific biologics, the association of clearance with therapeutic outcomes and the role of clearance monitoring and MIPD in patients with IBD. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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12 pages, 915 KiB

Open AccessReview

A Review of Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Receiving Combination Therapy

by Sanket Patel and Andres J. Yarur

J. Clin. Med. 2023, 12(20), 6577; https://doi.org/10.3390/jcm12206577 - 17 Oct 2023

Viewed by 1265

Abstract

Background: Inflammatory Bowel Disease (IBD) impacts millions worldwide, presenting a major challenge to healthcare providers and patients. The advent of biologic therapies has enhanced the prognosis, but many patients exhibit primary or secondary non-response, underscoring the need for rigorous monitoring and therapy optimization to improve outcomes. Objective: This narrative review seeks to understand the role of therapeutic drug monitoring (TDM) in optimizing treatment for IBD patients, especially for those on combination therapies of biologics and immunomodulators. Methods: A comprehensive synthesis of the current literature was undertaken, focusing on the application, benefits, limitations, and future directions of TDM in patients receiving a combination of biologic therapies and immunomodulators. Results: While biological therapies have improved outcomes, rigorous monitoring and therapy optimization are needed. TDM has emerged as a pivotal strategy, enhancing outcomes cost-effectively while reducing adverse events. While most data pertain to monotherapies, TDM’s applicability also extends to combination therapy. Conclusion: TDM plays a crucial role in the treatment optimization of IBD patients on combination therapies. Further research is needed to fully understand its potential and limitations in the broader context of IBD management. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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19 pages, 337 KiB

Open AccessReview

The Role of Low-Dose Oral Methotrexate in Increasing Anti-TNF Drug Levels and Reducing Immunogenicity in IBD

by Kathryn Demase, Cassandra K. Monitto, Robert D. Little and Miles P. Sparrow

J. Clin. Med. 2023, 12(13), 4382; https://doi.org/10.3390/jcm12134382 - 29 Jun 2023

Cited by 4 | Viewed by 1854

Abstract

Concomitant immunomodulation is utilised in combination with anti-TNF therapy for IBD primarily to increase drug levels and prevent anti-drug antibody formation. Whilst thiopurines have traditionally been the immunomodulator of choice in IBD populations, there are concerns regarding the long-term safety of the prolonged use of these agents: particularly an association with lymphoproliferative disorders. Given this, we have explored the existing literature on the use of low-dose oral methotrexate as an alternative immunomodulator for this indication. Although there is a lack of data directly comparing the efficacies of methotrexate and thiopurines as concomitant immunomodulators, the available literature supports the use of methotrexate in improving the pharmacokinetics of anti-TNF agents. Furthermore, low-dose oral methotrexate regimens appear to have comparable efficacies to higher-dose parenteral administration and are better tolerated. We suggest that clinicians should consider the use of low-dose oral methotrexate as an alternative to thiopurines when the primary purpose of concomitant immunomodulation is to improve anti-TNF pharmacokinetics. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

12 pages, 262 KiB

Open AccessReview

Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis

by Benjamin L. Gordon and Robert Battat

J. Clin. Med. 2023, 12(10), 3378; https://doi.org/10.3390/jcm12103378 - 10 May 2023

Cited by 3 | Viewed by 2174

Abstract

Therapeutic drug monitoring (TDM) is a useful strategy in ulcerative colitis (UC). Nearly a quarter of UC patients will experience acute severe UC (ASUC) in their lifetime, including 30% who will fail first-line corticosteroid therapy. Steroid-refractory ASUC patients require salvage therapy with infliximab, cyclosporine, or colectomy. Fewer data are available for the use of TDM of infliximab in ASUC. The pharmacokinetics of ASUC make TDM in this population more complex. High inflammatory burden is associated with increased infliximab clearance, which is associated with lower infliximab drug concentrations. Observational data support the association between increased serum infliximab concentrations, lower clearance, and favorable clinical and endoscopic outcomes, as well as decreased rates of colectomy. Data regarding the benefit of accelerated or intensified dosing strategies of infliximab—as well as target drug concentration thresholds—in ASUC patients remain more equivocal, though limited by their observational nature. Studies are underway to further evaluate optimal dosing and TDM targets in this population. This review examines the evidence for TDM in patients with ASUC, with a focus on infliximab. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

18 pages, 1325 KiB

Open AccessReview

Therapeutic Drug Monitoring of Subcutaneous Infliximab in Inflammatory Bowel Disease—Understanding Pharmacokinetics and Exposure Response Relationships in a New Era of Subcutaneous Biologics

by Robert D. Little, Mark G. Ward, Emily Wright, Asha J. Jois, Alex Boussioutas, Georgina L. Hold, Peter R. Gibson and Miles P. Sparrow

J. Clin. Med. 2022, 11(20), 6173; https://doi.org/10.3390/jcm11206173 - 19 Oct 2022

Cited by 11 | Viewed by 3150

Abstract

CT-P13 is the first subcutaneous infliximab molecule approved for the management of inflammatory bowel disease (IBD). Compared to intravenous therapy, SC infliximab offers a range of practical, micro- and macroeconomic advantages. Data from the rheumatological literature suggest that subcutaneous CT-P13 may lead to superior disease outcomes in comparison to intravenous infliximab. Existing studies in IBD have focussed on pharmacokinetic comparisons and are inadequately powered to evaluate efficacy and safety differences between the two modes of administration. However, emerging clinical trial and real-world data support comparable clinical, biochemical, endoscopic and safety outcomes between subcutaneous and intravenous infliximab in both luminal Crohn’s disease and ulcerative colitis. Across the available data, subcutaneous CT-P13 provides relative pharmacokinetic stability and higher trough drug levels when compared to intravenous administration. The clinical impact of this observation on immunogenicity and treatment persistence is yet to be determined. Trough levels between the two methods of administration should not be compared in isolation as any subcutaneous advantage must be considered in the context of comparable total drug exposure and the theoretical disadvantage of lower peak concentrations compared to intravenous therapy. Furthermore, target drug levels for subcutaneous CT-P13 associated with remission are not known. In this review, we present the available literature surrounding the pharmacokinetics of subcutaneous CT-P13 in the context of therapeutic drug monitoring and highlight the potential significance of these observations on the clinical management of patients with IBD. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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12 pages, 264 KiB

Open AccessReview

Therapeutic Drug Monitoring in Perianal Fistulizing Crohn’s Disease

by Mir Zulqarnain, Parakkal Deepak and Andres J. Yarur

J. Clin. Med. 2022, 11(7), 1813; https://doi.org/10.3390/jcm11071813 - 25 Mar 2022

Cited by 6 | Viewed by 2277

Abstract

Perianal fistulas are a common complication of Crohn’s disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn’s disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is an important unmet need. Given its emerging role in other phenotypes of Crohn’s disease, the use of TDM could also offer an opportunity to enhance the effectiveness of available therapies and improve outcomes in the subset of patients with PFCD receiving biologics. Overall, there is mounting evidence that higher anti-TNF drug levels are associated with better rates of “fistula healing”. However, studies have been limited by their use of subjective outcomes and observational designs. Ultimately, further interventional, randomized controlled trials looking into the relationship between drug exposure and fistula outcomes are needed. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

16 pages, 676 KiB

Open AccessReview

Therapeutic Drug Monitoring of Biologics in IBD: Essentials for the Surgical Patient

by Rodrigo Bremer Nones, Phillip R. Fleshner, Natalia Sousa Freitas Queiroz, Adam S. Cheifetz, Antonino Spinelli, Silvio Danese, Laurent Peyrin-Biroulet, Konstantinos Papamichael and Paulo Gustavo Kotze

J. Clin. Med. 2021, 10(23), 5642; https://doi.org/10.3390/jcm10235642 - 29 Nov 2021

Cited by 3 | Viewed by 2561

Abstract

Despite significant development in the pharmacological treatment of inflammatory bowel diseases (IBD) along with the evolution of therapeutic targets and treatment strategies, a significant subset of patients still requires surgery during the course of the disease. As IBD patients are frequently exposed to biologics at the time of abdominal and perianal surgery, it is crucial to identify any potential impact of biological agents in the perioperative period. Even though detectable serum concentrations of biologics do not seem to increase postoperative complications after abdominal procedures in IBD, there is increasing evidence on the role of therapeutic drug monitoring (TDM) in the perioperative setting. This review aims to provide a comprehensive summary of published studies reporting the association of drug concentrations and postoperative outcomes, postoperative recurrence (POR) after an ileocolonic resection for Crohn’s disease (CD), colectomy rates in ulcerative colitis (UC), and perianal fistulizing CD outcomes in patients treated with biologics. Current data suggest that serum concentrations of biologics are not associated with an increased risk in postoperative complications following abdominal procedures in IBD. Moreover, higher concentrations of anti-TNF agents are associated with a reduction in colectomy rates in UC. Finally, higher serum drug concentrations are associated with reduced rates of POR after ileocolonic resections and increased rates of perianal fistula healing in CD. TDM is being increasingly used to guide clinical decision making with favorable outcomes in many clinical scenarios. However, given the lack of high quality data deriving mostly from retrospective studies, the evidence supporting the systematic application of TDM in the perioperative setting is still inconclusive. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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10 pages, 562 KiB

Open AccessReview

A Practical Guide to Therapeutic Drug Monitoring of Biologic Medications for Inflammatory Bowel Disease

by Byron P. Vaughn

J. Clin. Med. 2021, 10(21), 4990; https://doi.org/10.3390/jcm10214990 - 27 Oct 2021

Cited by 4 | Viewed by 3616

Abstract

Therapeutic drug monitoring (TDM) is a useful strategy to optimize biologic medications for inflammatory bowel disease not responsive to standard dosing regimens. TDM is cost effective for anti-tumor necrosis factor agents in the setting of loss of response (reactive TDM). Optimizing drug dosing when patients are in remission (proactive TDM) may be beneficial in certain circumstances. However, frequently the serum drug concentration in isolation becomes the focus TDM. Additionally, the lines of reactive and proactive TDM can quickly blur in many common clinical settings. Physicians employing a TDM based strategy need to place the drug concentration in context with the inflammatory status of the patient, the underlying pharmacokinetics and pharmacodynamics of the drug, the risk of immunogenicity, and the therapeutic goals for the patient. Physicians should understand the limits of TDM and feel comfortable making therapeutic decisions with imperfect information. The goal of this narrative review is to provide a framework of questions that physicians can use to employ TDM effectively in practice. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

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