Therapeutic Drug Monitoring Of Infliximab Research Articles

A Bottom-Up Liquid Chromatography-Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Infliximab: Method Development, Comparison With 2 Enzyme-Linked Immunosorbent Assay Methods, and Evaluation of Anti-Drug Antibody Interference.

Therapeutic drug monitoring is recommended to optimize infliximab use and improve outcome in chronic inflammatory disorders. To describe a simple and affordable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure infliximab in serum. Infliximab was measured using winged stable isotope-labeled peptides as internal standards. Linearity, lower limit of measuring interval, limit of detection, precision, accuracy, carryover, and ion suppression were evaluated. Method comparison against 2 enzyme-linked immunosorbent assay (ELISA) methods (Remsima Monitor and IDKmonitor Infliximab) and anti-drug antibody (ADA) interference were evaluated using clinical specimens from inflammatory bowel disease patients (N = 237). Analytical run time and sample preparation time were 5 minutes per sample and 3 hours per batch, respectively. Analytical measurement interval and limit of detection were 0.50 to 50.0 μg/mL (R2 = 0.998) and 0.25 μg/mL, respectively. The intraday and interday imprecision percentage coefficients of variation were less than 6.1%. Accuracy was 94.2% to 98.7%. No significant ion suppression or carryover was observed. Infliximab concentrations measured by LC-MS/MS showed good agreement with those measured by Remsima Monitor (mean percentage difference, 5.7%; 95% CI, -1.2% to 12.6%) but were markedly lower than those measured by IDKmonitor (-32.6%; -35.8% to -29.4%), demonstrating significant bias between ELISAs. Although a good agreement between LC-MS/MS and ELISA was observed for ADA-negative samples (-3.5%; -12.8% to 5.9%), a significant bias was observed for ADA-positive samples (13.6%; 1.7% to 25.6%). This simple, fast, and affordable LC-MS/MS method for infliximab quantitation could improve standardization of infliximab quantitation and optimization of infliximab use in patients with high-titer ADA.

Fluorescence-Based Lateral Flow Immunoassay for Quantification of Infliximab: Analytical and Clinical Performance Evaluation.

Therapeutic drug monitoring of infliximab (IFX) can improve treatment outcomes; however, the temporal gap between drug concentration monitoring and subsequent availability restricts its practical application. To address this issue, an automated monitoring method, AFIAS IFX, was developed to rapidly and accurately analyze IFX concentration in blood. The analytical and clinical performances of this method were assessed to establish its clinical utility. The analytical performance of AFIAS IFX was evaluated according to Clinical and Laboratory Standard Institute guidelines. For clinical validation, AFIAS IFX was compared with 3 established enzyme-linked immunosorbent assay kits (LISA TRACKER, RIDASCREEN, and ImmunoGuide) using 100 consecutive samples from 28 patients treated with IFX. Passing-Bablok regression and Bland-Altman analyses were performed to compare the methods. The detection and quantification limits of AFIAS IFX were 0.12 and 0.20 mcg/mL, respectively. Furthermore, AFIAS IFX analyzed samples within 10 minutes for concentrations up to 50 mcg/mL, exhibiting reproducibility (coefficient of variation [CV] ≤7.8%) and accuracy (recovery 98%-101%) with serum, plasma, and whole blood samples. Clinically, it exhibited a good correlation with the 3 established enzyme-linked immunosorbent assay kits. For patients treated with Remicade (IFX), the Passing-Bablok regression slope was 1.001-1.259, with a mean difference of -1.48 to 0.28 mcg/mL. For patients treated with CT-P13, the Passing-Bablok regression slope was 0.974-1.254, with a mean difference of -2.44 to 0.15 mcg/mL. AFIAS IFX, a novel fluorescence-based lateral flow assay, exhibited excellent performance in analyzing IFX trough levels and is a potentially powerful tool for therapeutic drug monitoring in clinical settings, with opportunities for further development.

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

المراقبة الدوائية العلاجية للإنفلاكسيماب في المرضى العراقيين المصابين بمرض كرون

Background: Inflammatory bowel disease (IBD) is a collection of chronic, recurrent inflammatory illnesses of the gastrointestinal system, including Crohn's disease (CD). Infliximab is one of the biological medications used to treat CD. Therapeutic drug monitoring has evolved as a treatment in IBD, aiming to optimize benefit while meeting more demanding, objective end criteria. Objective: To determine the achievement of target trough level (TL), develop anti-drug antibodies (ADAs) to infliximab, assess response to therapy, and study TL relations with different variables. Methods: The present study was cross-sectional and conducted from May 2022 to November 2022. It included 40 CD patients allotted into 2 groups: group 1 patients achieved the TL target, and group 2 patients did not achieve the TL target. Results: Twenty-two patients achieved target TL, while 18 patients did not. Dose escalation is recommended for 11 patients, switching therapy for 15 patients, and continuing the same dosage regimen for 14 patients. In addition, erythrocyte sedimentation rate, C-reactive protein, serum calprotectin and ADAs were significantly lower in patients who achieved target infliximab TL. Only serum calprotectin can be used to predict the achievement of the target TL of infliximab. Conclusions: Therapeutic drug monitoring of infliximab to determine the TL and ADAs can help to explain why some patients do not respond to this drug. Serum calprotectin may be used as a novel marker to predict the TL and response to infliximab.

Highly sensitive therapeutic drug monitoring of infliximab in serum by targeted mass spectrometry in comparison to ELISA data

BackgroundPresently, antibody concentration measurements for patients undergoing treatment are predominantly determined by ELISA, which still comes with known disadvantages. Therefore, our aim was to establish a targeted mass-spectrometric assay enabling the reproducible absolute quantification of peptides from the hypervariable and interaction regions of infliximab.MethodsPeptides of infliximab were measured post-trypsin digestion and subsequent separation on a Vanquish Horizon UHPLC coupled to a TSQ Altis Triple-Quad mass spectrometer. Normalization and absolute quantification were conducted using stable isotope-synthesized peptides. Calibration curves covering a range of 0.25-50 µg/ml were employed for quantitation.ResultsWe demonstrated the substantial influence of peptide selection, choice of hydrolase for digestion, and digestion time on absolute peptide yield (28–44% for peptide 1 and 64–97% for peptide 2). Furthermore, we showed that the generated calibration curves for absolute quantification were highly reproducible and robust (LLOQ1 0.72 µg/ml and LLOQ2 1.00 µg/ml) over several months. In comparison to ELISA values, the absolute values obtained by mass spectrometry often yielded lower results for both targeted peptides.ConclusionsIn this study, a semi-automated workflow was employed and tested with 8 patients and corresponding replicates (n = 3–4). We demonstrated the robust implementation of calibration curves for the absolute quantification of infliximab in patient samples, with coefficients of variation ranging from 0.5 to 9%. Taken together, we have developed a platform enabling the rapid (2 days of sample preparation and 30 min of measurement time per sample) and robust quantification of Infliximab antibody concentration in patients. The use of mass spectrometry also facilitates the straightforward expansion of the method to include additional antibody peptides.

COMPARING REAL-WORLD OUTCOMES, MEASURED AS 12 AND 24-MONTH IBD-RELATED SURGERIES, BETWEEN INFLIXIMAB DOSE OPTIMIZED PATIENTS USING THERAPEUTIC DRUG MONITORING (TDM) VS AN UNOPTIMIZED CONTROL GROUP, IN A LARGE US COMMUNITY-BASED GASTROENTEROLOGY PRACTICES

Abstract BACKGROUND Anti-TNFs such as infliximab (IFX) continue to be the standard of care to treat moderate-to-severe IBD. Remission and reducing detrimental outcomes are achievable goals when therapeutic drug monitoring (TDM) is implemented to assist with IFX therapy optimization. TDM aids in achieving & maintaining adequate drug exposure to avoid loss of response by offering actionable information to guide treatment adjustments. The value of TDM has been described in numerous studies which show that optimization of anti-TNFs correlates with improved clinical outcomes & the use of TDM is recommended by IBD guidelines and expert consensus. A potential evidence gap is the lack of real-world outcomes data when Anser®, a TDM test, is implemented in a community setting. OBJECTIVE Describe & compare the real-world outcomes, measured as IBD-related surgeries, in IFX dose optimized patients using Anser® TDM as part of ongoing IBD care as compared to a no TDM control group in a community-based practice setting. METHODS De-identified patient charts from a US-based community gastroenterology practice were analyzed for all patients (ages 8 to 89) treated with IFX from 2016 to 2022. Matching records to Prometheus Laboratories test results were then tokenized. Two cohorts were structured, Anser TDM as part of ongoing IBD care & no TDM. Groups were matched by propensity score, baseline disease, demographics, and comorbidities for comparison. Real-world outcomes were accessible via Lynx.MD online database. Analysis was conducted, stratifying patients as all IFX patients or anti-TNF naïve patients (TNF-N), to compare the percentage of IBD-related surgeries for 12 or 24-month outcomes. IBD surgeries were recorded in patient charts as colectomies, surgeries for fistula, bowel perforations, drainage of abscesses, adhesiolysis and other surgical bowel procedures. Statistical analysis was completed by Lynx.MD. RESULTS The size of Anser TDM (n= 235 to 337) and no TDM (n= 223 to 321) cohorts varied depending on the analysis criteria. Crohn’s disease was majority (2/3) and median age ranged from 36 to 39. For all IFX patients the 12-month outcomes of any IBD surgery was 1.2% for Anser TDM vs 6.5% for no TDM (5.4%, P=0.001). For TNF-N patients, the rate was 1% and 6.8%, respectively (5.7%, P=0.001). The results for 24-month outcomes for all IFX patients were 4.1% for Anser TDM vs 9.8% for no TDM (4.1%, p=0.016), and 4.3% vs 9% respectively for TNF-N (4.8%, P=0.06). CONCLUSIONS Real-world outcomes data for 12 and 24-months demonstrate that the Anser IFX TDM group had significantly lower rates of IBD surgeries for all patients, including for 12-month outcomes in TNF-N. This finding provides the first analysis, on Anser® TDM used to optimize patient’s IFX dosing, in comparison to a matched cohort of no TDM patients within the same community gastroenterology clinic setting.

P851 Therapeutic drug monitoring of infliximab and adalimumab versus clinical control during maintenance therapy in patients with Inflammatory Bowel Disease

Abstract Background Although it is known that the levels of infliximab or adalimumab are correlated with clinical response, there is controversy about the best strategy to follow in patients with Inflammatory Bowel Disease (IBD) in remission and undergoing maintenance treatment. Methods We conducted a randomized, prospective, single-blinded, and multicentre trial in patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) who have remained in clinical remission for at least 12 weeks and are receiving adalimumab (ADA) or infliximab (IFX) as maintenance treatment. Patients were assigned to two groups. In the first group, patient management was done considering therapeutic drug monitoring (TDM). In the second, according to usual clinical practice (CP). The optimal serum range was within 3-7µg/ml and 5-8µg/ml for IFX and ADA respectively, based on the use of Promonitor-IFX, and Promonitor-ADL kits. The primary endpoint was to maintain patients in clinical remission (target >16% between both groups at 12 months) and diminish the frequency of flare-ups. Results In total, 209 patients were randomized, 29 UC (27.6%), 76 CD (72.4%) as the clinical practice group, and 24 UC (23.1%), 80 CD (76.9%) as the drug monitoring therapeutic group. Infliximab was administered in 105 patients and adalimumab in 104. Remission at the end of the study was achieved in 98.1% of the proactive dosing group and 90.5% of the clinical practice group (p=0.02), with a difference between both groups of 7.6%. The number of flare-ups was 1.3/10 patient-years in the TDM group and 2.4/10 patient-years in the CP group. The IRR of flare-up throughout the study was 0.71 (95% CI 0.32 – 1.55). In the group with IFX: IRR = 0.56 (95% CI 0.08 – 3.81) and with ADA: 0.78 (95% CI 0.29-2.16). The changes made in the drug dose are shown in Table 1. Conclusion Differences were found in favour of the TDM group, with increasing remission rates (7.6%) and half number of flare-ups. However, the pre-established effectiveness remission target (16%) was not met. In the subgroup of patients with Infliximab, management through TDM seems to have an advantage over usual clinical control.

P565 Capillary blood based self-collection device for infliximab therapeutic drug monitoring

Abstract Background Patient friendly new devices may improve therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD). Our objective was to evaluate an infliximab (IFX) precision guided dosing tool from capillary blood collected using an upper-arm self-collection device amongst IBD patients and compare its performances to gold standard venous blood collected using venipuncture. Methods Patients under maintenance therapy with IFX were recruited from a single IBD center and enrolled in the BEST (Bayesian Estimates Sustaining Trough) study. BEST is a prospective real world evidence clinical utility study to establish the value of an IFX Bayesian forecasting tool in the optimal management of IBD. Blood specimens were collected prospectively, at midcycle or at trough. Capillary blood specimens were collected using an upper arm self-collection device (Tasso Inc., Seattle, WA) connected to a serum separator tube. Paired venous blood was collected using venipuncture. IFX concentrations and antibodies to IFX (ATI) status were measured using drug tolerant homogenous mobility shift assay, albumin levels were measured using nephelometry. IFX Clearance was calculated using nonlinear mixed effect model with Bayesian priors. Statistical analysis consisted of Deming regression. Results Overall, 27 patients (n=9 with UC, mean age=37 years, weight=79 Kg) were enrolled. Median IFX dosing was 10 mg/Kg, and median dosing frequency every 6 weeks. A total of n=58 serum pairs isolated from capillary and venous blood were tested. PK profiles measured from venous blood were optimal during maintenance with no immune response detected (ATI < 3.1 U/mL) and most patients had IFX concentration at trough above 5 µg/mL (98%, median 15.4 µg/mL IQR: 10.9-28.0 µg/mL) and low Clearance (< 0.294 L/day: 89%; median 0.200 L/day IQR: 0.170-0.248 L/day). IFX concentrations and Clearance levels were comparable between venous and capillary blood with high correlation (R2= 0.975; slope =0.928; and R2=0.978; slope =1.035, respectively) (figure). In capillary blood specimens collected at midcycle (median 14 days before the next infusion, n=12 pairs), median IFX concentration was 38.3 µg/mL (IQR: 31.2-64.7 µg/mL) and declined to 21.9 µg/mL (IQR: 14.1-44.5 µg/mL) at trough. There was a high correlation between forecasted and measured trough concentrations in capillary blood (R2=0.925; Deming’s slope=1.093). Similar results were observed with venous blood pairs (R2=0.983; Deming’s slope=1.024). Conclusion IFX therapeutic drug monitoring using patient self-collection of capillary blood performed as well as standard venous blood measurement. This collection method may facilitate the implementation of point of care TDM in clinical practice.

The impact of proactive versus reactive drug monitoring of infliximab on treatment outcomes in patients with crohn’s disease

Background Therapeutic drug monitoring (TDM) plays a crucial role in the management of Crohn’s disease (CD) patients receiving infliximab (IFX). While reactive TDM has been more commonly utilized previously, recent research suggests that proactive TDM may offer greater benefits for patients. Objective To compare treatment outcomes among patients receiving different monitoring modalities of IFX. Methods This was a retrospective cohort study that enrolled 142 CD patients who initiated IFX therapy at the First Affiliated Hospital of Nanjing Medical University from January 2014 to June 2021. The patients were divided into a reactive (n = 43) and proactive (n = 99) group. The outcome measures included sustained clinical response and remission rates, biological remission rates, endoscopic response and remission rates achieved in both groups at weeks 30 and 54. The incidence of adverse events (AEs), changes in IFX trough concentrations (TCs) and treatment adjustments within 54 weeks were also evaluated. Results Kaplan-Meier analysis demonstrated that the proactive group exhibited significantly higher cumulative probabilities of sustained clinical response, sustained clinical remission, and endoscopic response by Week 54. Compared to the reactive group, patients in the proactive group achieved significantly reduced rates of AEs-related hospitalization and surgery. After adjusting treatment strategies, the median concentration and the proportion of patients achieved an effective therapeutic concentration (TC > 3 μg/mL) at Week 54 was both significantly higher in the proactive group. Conclusions Proactive TDM of IFX plays a more crucial role in timely adjustment of treatment strategies and maintenance of effective concentrations, thereby contributing to the outcomes for CD patients.

Comparative Evaluation of Four Commercially Available Immunoassays for Therapeutic Drug Monitoring of Infliximab and Adalimumab.

Therapeutic drug monitoring (TDM) of anti-TNF-α is an important tool in clinical practice for inflammatory diseases. In this study, we have evaluated the performance of several assays for drug and antidrug antibodies (ADA) measurement in the serum. 50 sera from patients treated with infliximab (IFX) and 49 sera from patients treated with adalimumab (ADAL) were monitored with four immunoassays. We have compared Promonitor, i-Track10®, and ez-track1 assays to our gold standard Lisa Tracker® ELISA using Cohen's kappa, Passing-Bablok, and Bland-Altman analysis. The qualitative analysis evaluated by Cohen's kappa values found for IFX measurements an "almost perfect" concordance for Promonitor, "moderate" for i-Track10® and "substantial" for ez-Track1. For ADAL, kappa values were "moderate" for all tested methods. For anti-IFX, kappa values were "almost perfect" for Promonitor, "fair" for i-Track10®, and "substantial" for ez-Track1. For anti-ADAL, kappa values were "almost perfect" for all three assays. For quantitative analysis of drug measurements, Pearson's r values were all above 0.9 and Lin's concordance coefficients of all immunoassays were around 0.80. Performances of the four evaluated immunoassays were acceptable for TDM based on our laboratory experience. Nevertheless, concordance between the four methods for IFX measurement was not perfect and we recommend the use of the same assay for the follow-up of a given patient. The performances of the four immunoassays evaluated were similar and are acceptable for TDM based on our laboratory experience.

Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis.

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.

Surface plasmon resonance assays for the therapeutic drug monitoring of infliximab indicate clinical relevance of anti-infliximab antibody binding properties.

The therapeutic antibody infliximab (IFX) has improved the life quality of numerous autoinflammatory disease patients. However, IFX can trigger the generation ofanti-drug antibodies (ADA), whose optimal evaluation andmanagement are currently subject of controversial discussions. We present two novel surface plasmon resonance (SPR) biosensor assays for therapeutic drug monitoring of IFX and characterization of ADA and investigated the diagnostic value of ADA binding properties. IFX and ADA were quantified via developed SPR biosensor assays (IFXmon and ADAmon, respectively) and diagnostics-approved ELISA in sera from inflammatory bowel disease patients. Pre-analytic ADA enrichment with magnetic beads enabled analytical drug tolerance of the ADAmon assay. The dissociation ratio (DissR) as an index forADA:IFX binding stability was calculated from the SPR sensorgrams of ADA quantification runs. IFX levels determined by IFXmon assay and ELISA showed high agreement, whereas ADA quantification concordance between ADAmon assay and ELISA was poor. In patients, DissR was predominantly constant over time and differed significantly between therapy outcomes. A DissR cut-off of 1.524 indicated undetectable IFX levels with 71.4% sensitivity and 88.9% specificity. Additionally, the SPR reference surface was exploited as serum-individual negative control to check result plausibility within multi-sample run sequences. Overall, both SPR biosensor assays exhibited reliable quantitative performance with accuracies superior to their ELISA counterparts and precision inferior to ELISA only for ADAmon. DissR presented itself as promising ADA binding parameter and could contribute to both earlier and more tailored therapeutic decisions.

P595 Time of Therapeutic Drug Monitoring of infliximab during induction and its relationship with clinical remission in Inflammatory Bowel Disease

Abstract Background The usefulness of therapeutic drug monitoring(TDM) of infliximab during induction and its relationship with clinical outcome in patients with inflammatory bowel disease(IBD) is well established. However, the optimal time of monitoring in terms of clinical outcomes remains unclear. The aim is to evaluate the TDM at various times during induction and its association with clinical remission. Methods An observational, retrospective and single-centre study of patients with active disease ,Crohn’s disease (CD) or ulcerative colitis(UC), was performed. Induction treatment with infliximab 0, 2, 6 weeks was conducted and if there was response, maintenance therapy was provided. Antibody levels were measured in serum samples at week 2 and week 14 by using an enzyme-linked immunosorbent assay, within the therapeutic range(3-8 µg/ml). Patients were followed at least for one year or until loss of response. The clinical response was assessed in week 14 and week 52 by Harvey-Bradshaw Index in CD and Mayo Partial Index in UC. Results Out of 93 patients that were evaluated, 23 with UC(24.73%) and 70 with CD(75.27%,), 65 (69.89%) and 58 patients(62.37%) achieved remission at week 14 and week 52 respectively. Infliximab levels at week 14 but not at week 2 were significantly higher in patients who achieved clinical remission in both week 14 (5.8 vs 2.1 µg/ml; p=0.0002) as in week 52 (6.4 vs 1.9 µg/ml; p=0.0001). The levels at week 14, but not at week 2 had predictive value of remission, in both week 14 [OR 1,4 (CI 1.14-1.76) p=0.001] and week 52 [OR 1.4 (CI 1.15-1.87); p=0.001]. The patients with immunosuppressants at week 14 presented the highest rate of remission in week 52 (77.78 vs 52.63; p=0.014). The intensification of treatment was a negative factor to achieve remission both in week 14 and at week 52. Conclusion The levels of infliximab in week 14 are higher and have predictive value of clinical remission both in early (week 14) and long-term (week 52). Levels of infliximab in week 2 did not provide significant predictive value of clinical response. The use of immunosuppressants could be a favourable factor of clinical outcome.

P528 Effectiveness, Safety and Incremental Costs of Proactive Therapeutic Drug Monitoring of Infliximab in a Prospective Cohort of Inflammatory Bowel Disease Patients

Abstract Background The use of infliximab (IFX) is limited by low treatment persistence. Proactive therapeutic drug monitoring (pTDM) has been shown to increase the treatment persistence in inflammatory bowel disease (IBD) patients but the real-life data evaluating effectiveness, safety and costs of this approach are scarce. Therefore, the aim of this study was to assess survival on treatment, safety and costs of pTDM of IFX in the treatment of IBD. Methods IBD patients who started IFX in a referral centre using pTDM between January 2018 and March 2021 were included. The main outcomes were treatment persistence, adverse events and incremental costs of pTDM. IFX trough levels were assessed in the week 14 and subsequently every six months by commercially available ELISA kit (Ridascreen R-Biopharm) and with the cut-off level of 3μg/ml . Costs related to the measurements of levels and the costs of intensified treatment were calculated. The costs of pTDM were compared with costs of a modelled cohort using reactive TDM (rTDM) based on the data from the same cohort. The model used arbitrarily determined intensification regimen to 5mg/kg of IFX every 4 weeks in case of pharmacokinetically determined clinical or endoscopic loss of response. The calculation was performed for the first year of treatment. Results Overall, 99 patients with IBD were included (58 men – 59%; mean age 39,96 years, minimum-maximum, 20-73 years; 64% patients with Crohn′s disease; mean disease duration 103 months, minimum – maximum, 8-402 months). The treatment was intensified in 57 patients (58%). Overall treatment survival using pTDM was 87% at 6 months, 77% at one year, 66% at two years and 60% at both, the third and fourth year of treatment. There were no differences between patients on conventional regimen vs. intensified regimen with regards to adverse events. The costs related to pTDM in this cohort of 99 patients were € 90 306,56 while the costs of the modelled cohort using rTDM were € 24 846,30. The overall incremental costs were thus € 65 460,26 with mean costs per patient for the first year of treatment of € 661,21. Conclusion Proactive TDM of IFX results in a steady 60% treatment persistence beyond the second year of treatment with no impact on the safety. In the context of this solid treatment persistence, the incremental costs related to proactive TDM seem negligible when considering the costs of alternative biologicals used in case of loss of response to IFX.

P374 Therapeutic drug monitoring can guide the intravenous-to-subcutaneous switch of infliximab and vedolizumab: a pharmacokinetic simulation study

Abstract Background Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) were recently approved for maintenance treatment of patients with inflammatory bowel disease. However, further investigation is required to identify the patients most likely to benefit from intravenous (IV)-to-SC switch. We hypothesise that therapeutic drug monitoring (TDM) can guide the IV-to-SC switch. Methods Population pharmacokinetic (popPK) simulations were performed with previously published popPK models to explore the exposure profiles following various label and off-label IV-to-SC dosing scenarios (NONMEM 7.5).1-3 All virtual patients received IV IFX or VDZ at treatment weeks 0, 2, 6, 14, 22, and 30, and then switched to every two weeks (Q2W) or Q1W SC dosing. Results Following IV-to-SC switch according to label, the serum trough concentrations (Ctrough) will gradually increase over eight weeks (for IFX) and 16 weeks (for VDZ) before reaching the new steady state (SS) (Figure 1A-B). A linear relationship was observed between IV and SC Ctrough,ss for both drugs, allowing the prediction of SC Ctrough,ss hnbased on previous IV Ctrough,ss (Figure 1C-D). Administering the first SC dose four instead of eight weeks after the last IV dose will hit SS much faster (immediately for IFX and in two months for VDZ), thereby allowing earlier TDM and avoiding the risk of temporary underexposure (Figure 2). Patients on Q6W or Q8W IV infliximab can safely switch to Q2W SC infliximab without a meaningful decrease in Ctrough,ss, while patients on Q4W IV infliximab need Q1W SC infliximab (Figure 3A). Vedolizumab Ctrough,ss will always be maintained after switching to Q2W dosing (Figure 3B). While the Ctrough,ss target is easily maintained, it is more challenging to guarantee a stable eight-week averaged area under the concentration-time curve at SS (AUC8w,ss) upon switch. Surprisingly, switching to Q2W SC infliximab resulted in a lower AUC8w,ss than all possible IV infliximab dosing regimens used in clinical practice (Figure 3C). Only patients on Q4W IV vedolizumab should switch to Q1W SC dosing (Figure 3D). Depending on the belief whether it is Ctrough,ss or AUC that drives therapeutic response, patients who were on escalated IV dosing regimens may need Q1W SC to guarantee similar exposure before versus after switch (Table 1). Conclusion We performed popPK simulations to inform clinicians how to integrate TDM of IFX and VDZ into their clinical practice as a tool to monitor patients and guide decision-making on the optimal dosing strategy. REFERENCES: 1. EMA/CHMP/548703/2019. European Medicines Agency. 2019. 2. Rosario et al. Aliment Pharmacol Ther. 2015. 3. Rosario et al. J Crohns Colitis. 13, S357 (2019).

P765 Tolerating infliximab therapeutic drug monitoring without anti-drug antibodies – an argument for drug intolerant assays?

Abstract Background Therapeutic drug monitoring (TDM) helps guide clinical decision making in IBD patients on infliximab (IFX). There are two types of IFX TDM assays, drug tolerant and intolerant, where drug tolerant assays allow the detection of anti-drug antibodies (ADA) in the presence of drug and the latter does not. Our immunology laboratory is in the process of changing from a drug tolerant to a drug intolerant IFX assay for cost reasons. We aimed to determine whether this switch would affect the management of IBD patients with therapeutic IFX levels and detectable antibodies. Methods This was a retrospective cross-sectional study in a central London tertiary hospital. Patients were included if they had a diagnosis of Crohn’s Disease (CD), Ulcerative Colitis (UC), or Indeterminate colitis, and had therapeutic IFX levels (>3mg/ml) with detectable anti-drug antibodies (ADA) (>10 AU/ml) between January 2017 to March 2022. Electronic health records were reviewed to determine clinical actions within 4 months of drug measurement. Actions were categorized into three groups by two gastroenterology physicians: no change to management, ADA dependent or independent actions. ADA dependent decisions were immunomodulator (IMM) addition or discontinuation. ADA independent decisions included switching biologic, stopping IFX, or escalation/de-escalation in IFX dosing. Results A total of 2675 IFX TDM tests were performed for IBD patients in the defined period. Of these, 237 patients had 477 TDM results with therapeutic IFX levels and detectable ADA. Baseline characteristics were 36.8% (n=87) female, mean age (y) of 30 (SD ±13), and 66.2% (n=157) had CD. At the time of measurement, 76.1% (n=363/477) of patients were on combination therapy with an IMM and 23.1% (n=110) had active disease on physicians’ global assessment. Changes to management were made in 23.5% (112/477) of clinics following TDM, but only 2.5% (12/477) of actions were ADA dependent. There was no difference in high titer ADA group (>40 AU/ml) compared to low. Variables that significantly affected clinical decisions were IFX dose (p<0.001), IFX interval (p=0.004), and clinical disease activity (p<0.001). Conclusion 1 in 40 clinical decisions made in patients with therapeutic drug levels and detectable ADAs rely on knowing the ADA level. A cost analysis, with an appropriate IFX drug level threshold under which ADAs would be performed, assessing the proposed switch to a drug intolerant TDM assay would help determine whether cost savings outweigh missed decision-making opportunities.

Early Infliximab Clearance Predicts Remission in Children with Crohn's Disease.

Children with Crohn's disease have lower response rates to infliximab, lower infliximab levels, and higher infliximab clearance on weight-based dosing than adults. We hypothesize infliximab clearance is a predictive of later outcomes on infliximab in children with Crohn's disease. In this single-center retrospective study, data were collected from charts on diagnosis, anthropometry, routine labs, infliximab therapeutic drug monitoring, infliximab dosing, disease activity, and other treatments. With these data we generated a population pharmacokinetic model using non-linear mixed effects modeling and calculated infliximab clearance for each patient over time. Patients were classified as in remission, responder-only or non-responder at 5, 10 and 16months. Regression and ROC analyses were used to assess for early predictors of remission and response to infliximab. Eighty-five subjects were included, with a median follow-up of 22.3months (IQR 10.1-36.8). Our pharmacokinetic model showed infliximab clearance was positively associated with CRP and weight, while negatively associated with albumin. In regression analyses, early infliximab clearance was the only significant, consistent predictor of remission. A 0.1 L/day increase in infliximab clearance predicted remission with an OR between 0.179 and 0.426. Differences in dosing did not account for differences in outcome. Infliximab clearance alone had moderate predictive accuracy of remission, with an AUC between 0.682 and 0.738. Early infliximab clearance is strongly associated with remission in children with Crohn's disease. It may be useful as a marker of response in proactive therapeutic drug monitoring to guide early dose optimization and/or changes in treatment for betterment of long-term outcomes.

Performance of Remsima® Monitor Drug Level versus RIDASCREEN IFX Monitoring in therapeutic drug monitoring of infliximab in patients with inflammatory bowel disease: A study of diagnostic accuracy.

Therapeutic drug monitoring (TDM) is effective in optimizing the efficacy of infliximab in patients with inflammatory bowel disease (IBD). An affordable way of monitoring is in high demand. This study evaluated the analytical and clinical performances of the newly available Remsima monitor kits and compared them with the established enzyme-linked immunosorbent assay kits. The trough level of infliximab in patients with IBD treated with an infliximab originator (Remicade) or biosimilar compounds (Remsima and Remaloce) was measured using a Remsima® Monitor Drug Level (Remsima) kit at the Samsung Medical Center, Seoul, Korea. Twenty-six plasma samples were collected immediately before the infusion of infliximab from 18 patients with IBD (Remicade, n = 8; Remsima, n = 6; and Remaloce, n = 4). The intra-assay intraclass correlation coefficient (ICC) of the RIDA and Remsima kits was 0.951 (95% CI = 0.908–0.976) and 0.990 (95% CI = 0.981–0.995). The inter-assay ICC of infliximab trough level between the RIDA and Remsima kits was very high (R = 0.971; 95% CI = 0.935–0.987), and the mean difference between the kits was 1.458 (95% limits of agreement = −3.302 to 6.219). The intra- and inter-assay reliabilities of all types of infliximab did not show significant differences. Qualitative stratification revealed substantial similarities between the kits (weighted kappa = 0.798). This study indicated that the Remsima kit was reproducible and highly correlated with the RIDA kit.

Population Pharmacokinetics of Infliximab in Children with Juvenile Idiopathic Arthritis.

The recommended infliximab (IFX) dose in (pediatric) rheumatology practice is 3-6 mg/kg every 4-8 weeks. Higher dosage regimens (>10 mg/kg) of IFX are effective and safe. To optimize IFX treatment in patients with juvenile idiopathic arthritis (JIA), therapeutic drug monitoring might be beneficial. To support routine therapeutic drug monitoring of IFX and regimen optimization for patients with JIA, in-depth knowledge of the pharmacokinetic (PK) variability of IFX is needed. As soon as the optimal therapeutic drug ranges are known, PK model-based simulation can be used to individualize drug dosing recommendations. In this study, a population PK model for IFX is described for patients with JIA. Data including IFX trough concentrations and anti-IFX antibodies of 27 pediatric patients with JIA on IFX maintenance treatment were retrieved from electronic charts. Three population PK models from the literature were validated for the authors' data set using the nonlinear mixed-effects modeling program NONMEM. A novel population PK model was developed based on the study data. A total of 65 blood samples obtained after a median of 32 days after the last IFX infusion (interquartile range 28-42) were analyzed. The 3 published models underpredicted the observed trough concentrations. A newly developed one-compartment model best described the data corresponding to IFX serum concentration over time in patients with JIA. This study shows a novel PK model for IFX in patients with JIA. The data show that different PK models are needed for different age categories (children or adults) and different diseases.

P081 Therapeutic Drug Monitoring of infliximab in Crohn’s Disease: Cut-off points during maintenance therapy

Abstract Background Therapeutic drug monitoring of infliximab in Crohn’s disease is necessary to optimize treatments. However, infliximab serum levels are not well defined. The aim of the study was to find our cut-off of infliximab serum levels in Crohn’s disease patients in remission in clinical practice. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. Methods Observational, retrospective and single-center study of patients diagnosed with Crohn’s disease on maintenance therapy with infliximab from January 2019 to July 2020. Infliximab trough levels and antibodies to infliximab were measured at least three times, after 6 months of treatment. The tests were performed using enzyme linked immunosorbent assay. Clinical remission was defined using the Harvey Bradshaw index ≤4. The interpretation of data was by ROC analysis. Results 105 Crohn’s disease patients were included in the study, 57.1% men, with a median age at diagnosis of 26 years. The rest of the characteristics are in table 1. The best infliximab level cut-off point classifying patients in clinical remission was 4 μg/ml with an area under the curve of 0.801 (figure 1 and 2). Median infliximab trough levels were significantly higher when patients achieved clinical remission [4.8 (3–8) μg/ml] versus [0.59 (0.1–2.4) μg/ml]. In the multivariate analysis we observed that the variables age, time on infliximab treatment and time of disease evolution were associated with non-remission (table 2). Conclusion Infliximab levels are an objective parameter related to clinical remission in maintenance therapy in patients with Crohn’s disease. Our cut-off point associated with clinical remission was 4 μg/ml.