• Absolute quantification
• Infliximab
• Mass spectrometry
• TDM

• Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V. (3463)

• Biologic drugs failure
• Biologic therapy
• Drug level
• Inflammatory bowel disease therapy
• Therapy monitoring
• Thiopurine metabolism
• Thiopurine metabolite estimation

• Humans
• Tumor Necrosis Factor Inhibitors/therapeutic use
• Drug Monitoring
• Antibodies
• Purines/therapeutic use
• Inflammatory Bowel Diseases/epidemiology

• anti-TNF
• loss of response
• primary non-response
• switch out of class
• switch within class
• therapeutic drug monitoring

• drug dosage
• mass spectrometry
• personalized therapy
• precision medicine
• therapeutic drug monitoring

• Chromatography, Liquid
• Drug Monitoring
• Humans
• Infant, Newborn
• Precision Medicine
• Tandem Mass Spectrometry

• Genome Canada
• Ministry of Science and Higher Education of the Russian Federation
• Segal Family Foundation
• Terry Fox Research Institute
• Warren Y. Soper Charitable Trust

Immune checkpoint blockade (ICB) using anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of advanced cancer. However, ICB is effective for only a small fraction of patients, and biomarkers such as expression of PD-L1 in tumor or serum levels of CXCL11 have suboptimal sensitivity and specificity. Exposure–response (E-R) relationships have been observed with other therapeutic monoclonal antibodies. There are many factors influencing E-R relationships, yet several studies have shown that trough levels of anti-PD-1/PD-L1 correlated with clinical outcomes. However, the potential utility of anti-CTLA-4 levels as a biomarker remains unknown.

Serum was obtained at trough levels at weeks 7 and 12 (after doses 2 and 4) from patients with advanced melanoma who received ipilimumab alone (3 mg/kg every 3 weeks for four treatments) via an expanded access program (NCT00495066). We have successfully established a proteomics assay to measure the concentration of ipilimumab in serum using an liquid chromatography with tandem mass spectrometry-based nanosurface and molecular-orientation limited proteolysis (nSMOL) approach. Serum samples from 38 patients were assessed for trough levels of ipilimumab by the nSMOL assay.

We found that trough levels of ipilimumab were higher in patients who developed immune-related adverse events but did not differ based on the presence or absence of disease progression. We found that patients with higher trough levels of ipilimumab had better overall survival when grouped based on ipilimumab trough levels. Trough levels of ipilimumab were inversely associated with pretreatment serum levels of CXCL11, a predictive biomarker we previously identified, and soluble CD25 (sCD25), a prognostic biomarker for advanced melanoma, as well as C reactive protein (CRP) and interleukin (IL)-6 levels at week 7.

Our results suggest that trough levels of ipilimumab may be a useful biomarker for the long-term survival of patients with advanced melanoma treated with ipilimumab. The association of ipilimumab trough levels with pretreatment serum levels of CXCL11 and sCD25 is suggestive of a baseline-driven E-R relationship, and the association of ipilimumab trough levels with on-treatment levels of CRP and IL-6 is suggestive of response-driven E-R relationship. Our findings highlight the potential utility of trough levels of ipilimumab as a biomarker.

NCT00495066.

• CTLA-4 antigen
• biomarkers
• immunotherapy
• melanoma
• translational medical research
• tumor

Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.

• Therapeutic drug monitoring
• Inflammatory bowel disease
• Biologic therapies
• Loss of response
• Reactive
• Proactive

• Biological Products/therapeutic use
• Drug Monitoring
• Gastrointestinal Agents/adverse effects
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Quality of Life

• Crohn’s disease
• antibodies to infliximab
• antibody dynamics
• immunogenicity testing
• inflammatory bowel disease
• infliximab
• personalized medicine
• secondary loss of response
• therapeutic drug monitoring
• treatment failure
• ulcerative colitis

To assess the clinical and cost-effectiveness of therapeutic drug monitoring (TDM) based on serum adalimumab levels compared to standard of care in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

This was a non-inferiority, multicentric, non-randomized, pragmatic trial including adult patients diagnosed with moderate-to-severe, clinically stable rheumatic diseases treated with adalimumab. Consecutive patients were assigned 1:2 to the control (CG) or the intervention group (IG), based on the site of inclusion, and followed up for 18 months. Adalimumab serum levels were measured at each study visit and released to the IG only to modify dosing strategy. Data on disease activity, healthcare resource utilization and health-related quality of life (HRQoL) measured through the EQ-5D-5L were collected. Number of persistent and overall flares, time to first flare, days experiencing high disease activity, total direct costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated.

Of the 169 recruited patients, 150 were included in the analysis (52 and 98 patients in the CG and IG, respectively). The primary endpoint was not met as persistent flares were not significantly lower in the IG, although mean (SD) number of flares was numerically lower in the IG (0.67 [0.70] versus 0.90 [0.82], P = 0.073), respectively. Based on EQ-5D-5L utilities, HRQoL was significantly higher in the IG at 3 (P = 0.001) and 6 months (P = 0.035), which overall translated into 0.075 QALYs gained per patient for the IG at month 18. Overall, direct costs were significantly lower for the IG patients (€15,311.59 [4,870.04] versus €17,378.46 [6,556.51], P = 0.030), resulting in the intervention being dominant, leading to increased QALY at a lower overall cost

Adalimumab dose tapering based on TDM for rheumatic patients led to an increased quality of life and QALY gain and entailed lower costs, being a more cost-effective alternative than clinically guided management.

The online version contains supplementary material available at 10.1007/s40744-021-00345-5.

• Adalimumab
• Cost-effectiveness
• Rheumatic diseases
• Therapeutic drug monitoring

The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1^st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.

• adalimumab
• biosimilars
• clinical monitoring
• international standard
• potency
• product life-cycle
• unit

Monoclonal antibodies (mAbs) have been extensively developed over the past few years, for the treatment of various inflammatory diseases. They are large molecules characterized by complex pharmacokinetic and pharmacodynamic properties. Therapeutic drug monitoring (TDM) is routinely implemented in the therapy with mAbs, to monitor patients’ treatment response and to further guide dose adjustments. Serum has been the matrix of choice in the TDM of mAbs and its sampling requires the visit of the patients to laboratories that are not always easily accessible. Therefore, dried blood spots (DBS) and various microsampling techniques have been suggested as an alternative. DBS is a sampling technique in which capillary blood is deposited on a special filter paper. It is a relatively simple procedure, and the patients can perform the home-sampling. The convenience it offers has enabled its use in the quantification of small-molecule drugs, whilst in the recent years, studies aimed to develop microsampling methods that will facilitate the TDM of mAbs. Nevertheless, hematocrit still remains an obstacle that hinders a more widespread implementation of DBS in clinical practice. The introduction of novel analytical techniques and contemporary microsampling devices can be considered the steppingstone to the attempts made addressing this issue.

• DBS
• TDM
• VAMS
• inflammatory diseases
• mAbs
• microsampling

• drug concentrations, ulcerative colitis, crohn’s disease
• inflammatory bowel disease
• therapeutic drug monitoring

• Drug Monitoring
• Gastrointestinal Agents/adverse effects
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Interleukin-12
• Tumor Necrosis Factor-alpha

With the overspread use of measurement of serum levels of anti-tumor necrosis factor (TNF) agents (therapeutic drug monitoring, TDM), new therapeutic strategies have been used in the management of Crohn’s disease (CD). Different targets are correlated with increased levels of circulating drugs. Recent evidence demonstrated that higher serum levels of anti-TNF agents may be associated to better outcomes in perianal fistulizing CD (PFCD). Overall, patients with healed fistulas had higher serum levels of infliximab and adalimumab as compared to those with active drainage. This was demonstrated in some cohort studies, in induction and maintenance, in adults and children with PFCD. In this narrative review, authors summarize current evidence on the use of serum level measurement of anti-TNF agents and its correlation with perianal fistula healing in CD patients. Data on the use of TDM in PFCD is discussed in detail. The retrospective design of the studies and the lack of objective parameters to measure fistula healing are the main limitations of published data. Prospective studies, with central reading of objective radiological parameters, such as pelvic magnetic resonance imaging scores, can improve the level of evidence on the possible advantages of TDM in perianal fistula in CD and are warranted.

• Crohn disease
• Fistula
• Tumor necrosis factor-alpha

• ELISA
• Eculizumab
• Liquid-chromatography tandem mass spectrometry
• Rituximab
• Therapeutic drug monitoring

Biosimilars are replacing originator compounds due to their similar effectiveness, safety and pharmacokinetics. Our objective was to compare the differences in pharmacokinetics and clinical outcomes between the originator infliximab (Ifx) and the biosimilar CT-P13 in a patient cohort with inflammatory bowel disease (IBD). Our cohort study included 86 patients from a historical and a prospective cohort from the start of infliximab treatment to 22 weeks later. Serum infliximab, antidrug antibody levels and other serum biomarkers were measured at weeks 0, 2, 6, 14 and 22. Remission outcomes were evaluated at weeks 14 and 22. Drug levels were measured prospectively and analysed using MANOVA. Of the 86 patients, 44 (51%) and 42 (49%) were administered the originator and CT-P13, respectively. Originator trough levels were higher than the biosimilar trough levels (35 vs. 21, 20.1 vs. 11, 6.6 vs. 2.9 and 4.3 vs. 1.7 μg/mL at weeks 2, 6, 14 and 22, respectively). A post-hoc analysis demonstrated changes in mean serum drug levels over time (p < 0.001) and according to the drug employed (p = 0.001). At week 22, 13 (81%) patients administered the originator achieved clinical remission compared with 5 (19%) patients with the biosimilar (p = 0.02). None of the patients administered the originator withdrew from the treatment compared with 7 for the biosimilar. During the study, there were significant differences in serum infliximab levels between the originator and the CT-P13 in the patients with IBD. The clinical outcomes were influenced by the type of compound administered.

• Antibodies to infliximab
• Biologicals
• Biosimilars
• Crohn’s disease
• Infliximab
• Therapeutic drug monitoring
• Ulcerative colitis

• Antibodies/blood
• Biomarkers/blood
• Female
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/immunology
• Infliximab/administration & dosage
• Infliximab/immunology
• Male
• Treatment Outcome

• Adult
• Aged
• Antirheumatic Agents/administration & dosage
• Antirheumatic Agents/pharmacokinetics
• Arthritis, Rheumatoid/blood
• Arthritis, Rheumatoid/diagnosis
• Arthritis, Rheumatoid/drug therapy
• Certolizumab Pegol/administration & dosage
• Certolizumab Pegol/pharmacokinetics
• Dose-Response Relationship, Drug
• Drug Monitoring/methods
• Feasibility Studies
• Female
• Humans
• Male
• Middle Aged
• ROC Curve
• Randomized Controlled Trials as Topic
• Severity of Illness Index
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

Model-informed precision dosing (MIPD) software tools are used to optimize dosage regimens in individual patients, aiming to achieve drug exposure targets associated with desirable clinical outcomes. Over the last few decades, numerous MIPD software tools have been developed. However, they have still not been widely integrated into clinical practice. This study focuses on identifying the requirements for and evaluating the performance of the currently available MIPD software tools. First, a total of 22 experts in the field of precision dosing completed a web survey to assess the importance (from 0; do not agree at all, to 10; completely agree) of 103 pre-established software tool criteria organized in eight categories: user-friendliness and utilization, user support, computational aspects, population models, quality and validation, output generation, privacy and data security, and cost. Category mean ± pooled standard deviation importance scores ranged from 7.2 ± 2.1 (user-friendliness and utilization) to 8.5 ± 1.8 (privacy and data security). The relative importance score of each criterion within a category was used as a weighting factor in the subsequent evaluation of the software tools. Ten software tools were identified through literature and internet searches: four software tools were provided by companies (DoseMeRx, InsightRX Nova, MwPharm++, and PrecisePK) and six were provided by non-company owners (AutoKinetics, BestDose, ID-ODS, NextDose, TDMx, and Tucuxi). All software tools performed well in all categories, although there were differences in terms of in-built software features, user interface design, the number of drug modules and populations, user support, quality control, and cost. Therefore, the choice for a certain software tool should be made based on these differences and personal preferences. However, there are still improvements to be made in terms of electronic health record integration, standardization of software and model validation strategies, and prospective evidence for the software tools’ clinical and cost benefits.

• model-informed precision dosing
• pharmacometrics
• software tool
• target concentration intervention
• therapeutic drug monitoring

Biologicals introduced a major shift in the treatment of patients suffering from inflammatory bowel diseases. Despite providing a tight disease control for many patients, a considerable proportion of patients will fail to respond favorably to treatment or will lose response over time. Therapeutic drug monitoring emerged as a valuable tool to guide clinical decision making as serum drug concentrations have been linked to outcomes. Focusing on mucosal healing as the ultimate treatment goal, different drug concentration thresholds to achieve this outcome have been identified in the literature and are summarized in this review. For therapeutic drug monitoring to be successful in guiding clinical decision making, the used assay, the sampling time point, and the outcome that is aimed for should be taken into account when interpreting drug concentration thresholds. Awareness of these essential aspects among clinicians will improve the implementation of therapeutic drug monitoring and aid in making an evidence‐based decision.

• Quantum Blue® Adalimumab
• adalimumab
• therapeutic drug monitoring

Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.

• exposure-response
• infliximab
• pharmacometrics
• population pharmacokinetics-pharmacodynamics
• ulcerative colitis

The past decade has brought substantial advances in the management of inflammatory bowel diseases (IBD). The introduction of tumor necrosis factor (TNF) antagonists, evidence for the value of combination therapy, the recognition of targeting lymphocyte trafficking and activation as a viable treatment, and the need for early treatment of high-risk patients are all fundamental concepts for current modern IBD treatment algorithms. In this article, authors review the existing data on approved biologicals and small molecules as well as provide insight on the current positioning of approved therapies. Patient stratification for the selection of specific therapies, therapeutic targets and patient monitoring will be discussed as well. The therapeutic armamentarium for IBD is expanding as novel and more targeted therapies become available. In the absence of comparative trials, positioning these agents is becoming difficult. Emerging concepts for the future will include an emphasis on the development of algorithms which will facilitate a greater understanding of the positioning of novel biological drugs and small molecules in order to best tailor therapy to the patient. In the interim, anti-TNF therapy remains an important component of IBD therapy with the most real-life evidence and should be considered as first-line therapy in patients with complicated Crohn’s disease and in acute-severe ulcerative colitis. The safety and efficacy of these ‘older’ anti-TNF therapies can be optimized by adhering to therapeutic algorithms which combine clinical and objective markers of disease severity and response to therapy.

• Inflammatory bowel disease
• Small molecule
• Positioning
• Biologic
• Therapeutic

• Biological Factors/therapeutic use
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/immunology
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Crohn Disease/immunology
• Guideline Adherence
• Humans
• Immunotherapy/methods
• Immunotherapy/standards
• Practice Guidelines as Topic
• Severity of Illness Index
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/immunology

• Azathioprine
• Biologics
• Inflammatory bowel disease
• Pediatrics
• Therapeutic drug monitoring
• Treatment

• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/blood
• Antibodies, Monoclonal, Humanized/therapeutic use
• Azathioprine/administration & dosage
• Azathioprine/blood
• Azathioprine/therapeutic use
• Biological Products/administration & dosage
• Biological Products/blood
• Biological Products/therapeutic use
• Child
• Drug Monitoring/methods
• Gastrointestinal Agents/administration & dosage
• Gastrointestinal Agents/blood
• Gastrointestinal Agents/therapeutic use
• Humans
• Inflammatory Bowel Diseases/blood
• Inflammatory Bowel Diseases/drug therapy
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Ustekinumab/administration & dosage
• Ustekinumab/blood
• Ustekinumab/therapeutic use

• anti-TNF
• rheumatoid arthritis
• treatment

• Adalimumab
• Antirheumatic Agents
• Arthritis, Rheumatoid
• Humans