Infliximab Trough Concentrations Research Articles

Simulated cost-effectiveness of a novel precision-guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy.

Patients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS). We developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4-week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity, scenario, and probabilistic sensitivity analyses (PSA). PGD was the cost-effective IFX dosing strategy with an ICER of 122,932 $ per quality-adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One-way sensitivity analysis demonstrated that the cost-effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results. PGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost-effective under conservative assumptions.

The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066L/h/46.4kg, 0.0055L/h/46.4kg, 0.0081L/h/46.4kg, 0.0029L/h/46.4kg, 0.6750L/46.4kg, and 1.19L/46.4kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

Performance of Eight Infliximab Population Pharmacokinetic Models in a Cohort of Dutch Children with Inflammatory Bowel Disease.

Efficacy of infliximab in children with inflammatory bowel disease can be enhanced when serum concentrations are measured and further dosing is adjusted to achieve and maintain a target concentration. Use of a population pharmacokinetic model may help to predict an individual's infliximab dose requirement. The aim of this study was to evaluate the predictive performance of available infliximab population pharmacokinetic models in an independent cohort of Dutch children with inflammatory bowel disease. In this retrospective study, we used data of 70 children with inflammatory bowel disease (443 infliximab concentrations) to evaluate eight models that focused on infliximab pharmacokinetic models in individuals with inflammatory bowel disease, preferably aged ≤ 18 years. Predictive performance was evaluated with prior predictions (based solely on patient-specific covariates) and posterior predictions (based on covariates and infliximab trough concentrations). Model accuracy and precision were calculated with relative bias and relative root mean square error and we determined the classification accuracy at the trough concentration target of ≥ 5 mg/L. The population pharmacokinetic model by Fasanmade was identified to be most appropriate for the total dataset (relative bias before/after therapeutic drug monitoring: -20.7%/11.2% and relative root mean square error before/after therapeutic drug monitoring: 84.1%/51.6%), although differences between models were small and several were deemed suitable for clinical use. For the Fasanmade model, sensitivity and specificity for maximum posterior predictions for the next infliximab trough concentration to be ≥ 5 mg/L were respectively 83.5% and 80% with an area under the receiver operating characteristic curve of 0.870. In our paediatric cohort, various models provided acceptable predictive performance, with the Fasanmade model deemed most suitable for clinical use. Model-informed precision dosing can therefore be expected to help to maintain infliximab trough concentrations in the target range.

VALIDATION OF AN INFLIXIMAB POPULATION PHARMACOKINETIC MODEL FOR MAINTENANCE DOSING IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract INTRODUCTION The use of infliximab has revolutionized the care of pediatric patients with inflammatory bowel disease (IBD); however, infliximab may lose efficacy over time during the maintenance phase and the use of therapeutic drug monitoring has been advocated to improve response rates. A population pharmacokinetic (popPK) model using infliximab concentrations, common clinical biomarkers, and demographic information to predict future infliximab concentrations would be clinically invaluable. Previous popPK models such as the Buurman [1] and Fasanmade [2] exist, but their utility, accuracy, and predictive values have not been clinically validated. This study aims to validate a reliable set of covariates for an infliximab popPK model that will predict maintenance drug concentrations and guide treatment decisions for children with IBD. METHODS This retrospective study included 134 pediatric patients with 503 infliximab trough concentrations between 5 and 21 years of age, seen at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at UH Rainbow Babies and Children’s Hospital between January 1, 2008 and December 31, 2018. We recorded the patients' therapeutic infliximab trough concentrations and other clinical and demographic factors. In previous work, we refit published popPK models using induction phase data. Here, we refit our originally constructed one-compartment model based on induction phase data, the Cleveland Model, with maintenance phase data to yield the Cleveland Refit model. We then tested six different models: Buurman (B), Buurman Refit (BR), Fasanmade (F), Fasanmade Refit (FR), Cleveland (C), and Cleveland Refit (CR). Each model was evaluated on root mean square error (RMSE), mean percent error (MPE), and accuracy of the predicted infliximab concentration. We defined accuracy as the percentage of samples each model correctly predicted to be on the same side of 5 ug/mL, which is our clinical trough target. RESULTS On the first infliximab concentration following the induction phase, published models refit on induction phase data (BR, FR) have higher accuracy but also higher RMSE than published models. In contrast, the CR model was refit on maintenance phase data and has higher accuracy (71.1% vs 66.7%) and lower RMSE (6.8 vs 7.8 ug/mL) and MPE (-5% vs 10%) than the previous induction-only model. CONCLUSIONS The CR model improved upon the performance of the induction-only models tested on this cohort. This study suggests refit popPK models on a specific patient population work well for predicting maintenance phase infliximab concentrations, and may be useful for personalization of dose of frequency for pediatric patients with IBD. Further validation with external data in a multicenter, prospective study is needed. References 1) https://doi.org/10.1111/apt.13299 2) https://doi.org/10.1016/j.clinthera.2011.06.002

P960 Comparison of clinical outcomes by induction therapy response status in patients with Inflammatory Bowel Disease (IBD) treated with subcutaneous (SC) versus intravenous (IV) infliximab (IFX): Post hoc analysis of a pivotal, randomised controlled trial

Abstract Background Clinical associations between initial response and long-term outcome are well established for IV IFX in IBD.1,2 In 2020, SC IFX was approved in Europe for treating moderate-to-severe Crohn’s disease (CD) or ulcerative colitis (UC), based on a pivotal randomised trial (NCT02883452) comparing SC and IV IFX.3 This post hoc analysis investigated clinical outcomes in patients (pts) treated with SC or IV IFX, by response to IV IFX induction. Methods In the pivotal trial, adults with active CD or UC received IV IFX induction (5 mg/kg; Week [W] 0 and W2), before randomisation to SC (n=66) or IV (n=65) arms. W6 clinical response (≥70-point decrease in Crohn’s Disease Activity Index [CDAI] score [CD]; ≥2-point decrease in partial Mayo score with ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1 [UC]) was a stratification factor. The SC arm received SC IFX (120/240 mg for pts weighing <80/≥80 kg) every 2 weeks from W6–54; the IV arm received IV IFX 5 mg/kg every 8 weeks (W6–22), then switched to SC IFX (W30–54). Rates of clinical remission (CDAI score <150 [CD]; partial Mayo score ≤1 [UC]) and trough IFX concentrations (Ctrough) were assessed at W6, W30 and W54. Analyses were descriptive. Results There were 101 induction responders (IRs) to IV IFX, who were randomised to the SC arm (n=49, 74.2%; SC-IR subset) or the IV arm (n=52, 80.0%; IV-IR subset). Correspondingly, there were 17 (25.8%) and 13 (20.0%) induction non-responders (INRs; SC-INR and IV-INR subsets, respectively). In both study arms, IRs had higher clinical remission rates than INRs at both W30 and W54 (Figure A). Comparing by formulation, the SC-INR subset had nearly twice the W30 clinical remission rate of the IV-INR subset (58.8% vs. 30.8%; p=0.159 [Fisher exact test]). In addition, IV-INR subset clinical remission rates numerically increased after pts switched to SC IFX (W30: 30.8% vs. W54: 46.2%; p=0.476 [McNemar test]). These observations were generally consistent with Ctrough findings (Figure B); median Ctrough in the IV-INR subset increased from 1.5 to 18.3 µg/mL (p=0.005 [Wilcoxon signe-drank test]) after switching to SC IFX. Conclusion Findings suggested associations between initial response to IFX induction therapy and positive long-term outcomes for both SC and IV IFX, and supported potential benefits with SC IFX maintenance therapy for INRs, compared with the option of IV IFX maintenance. Given the post hoc nature of the analysis and the small analysis population (thus statistical inconclusiveness), investigation in larger studies is warranted. 1Murthy SK et al. Inflamm Bowel Dis 2015;21:2090–6. 2Wong ECL et al. J Crohns Colitis 2021;15:1114–9. 3Schreiber S et al. Gastroenterology 2021;160:2340–53.

P684 Using a pharmacokinetic simulation model to determine the optimal infliximab intensification strategy to address loss of response in inflammatory bowel disease

Abstract Background The optimal dose intensification strategy to address loss of response associated with low infliximab levels remains uncertain. Favorable associations between higher infliximab levels and objective endpoints imply that post-intensification trough and treatment targets may have utility. This simulation study aimed to identify intensification strategies capable of achieving post-intensification trough thresholds associated with aspirational treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Methods A previously published infliximab pharmacokinetic model, applied to 200 simulated patients, identified those with subtherapeutic(<3.00mg/L) trough levels after 30-weeks of standard dosing, and subsequently applied ten dose intensification strategies (Figure 1) over a further 32 weeks. The proportion of simulations achieving infliximab trough thresholds associated with endoscopic remission (CD >9.7mg/L; UC >7.5mg/L) was the primary outcome, with clinical improvement (CD >7.0mg/L; UC >3.7mg/L) and perianal fistula healing (CD >10.1mg/L) representing secondary outcomes. Outcomes were stratified by intensity of dose intensification, with five deemed intensive (>10mg/kg 8-weekly). The impact of pre-intensification antibodies to infliximab (ATI) on post-intensification trough levels was also evaluated. Results The median pre-intensification infliximab trough level was 0.91mg/L (IQR 1.31). Intensive intensification strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (UC: 34.76 v 10.56%, CD: 25.80 v 4.92%), clinical improvement (UC: 61.40 v 34.52%, CD: 39.58 v 12.12%) and perianal fistula healing (24.70 v 4.50%, all p<0.01) than standard intensification strategies (Figure 2). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest trough levels (all p<0.01). Patients simulated to have ATI prior to dose intensification had lower median infliximab trough levels at weeks 30/32 (3.38 mg/L, IQR 5.52 mg/L) compared to those without ATI (3.89 mg/L IQR 6.14 mg/L) across all dose intensification strategies (p=0.015). Conclusion This simulation-based analysis highlights the potential of using post-intensification trough level targets to guide dosing strategy and intensity. Combined high-dose, interval-shortened strategies appear to achieve higher infliximab levels, which may be important in the pursuit of stringent endpoints such as endoscopic remission and fistula healing. These findings require validation across real-world cohorts.

Identifying risk factors of anti-TNF induced skin lesions and other adverse events in paediatric patients with inflammatory bowel disease.

While higher infliximab (IFX) trough concentrations (TCs) are associated with better outcomes in patients with inflammatory bowel disease (IBD), they could pose a risk for adverse events (AEs), including IFX-induced skin lesions. Therefore, we studied correlations between IFX TCs and occurrence of AEs in paediatric IBD patients. In this single-centre study, all children with Crohn's disease (CD) and ulcerative colitis (UC) receiving IFX maintenance therapy who underwent proactive drug monitoring between March 2015 and August 2022 were included. IFX doses/intervals/TCs and patient characteristics were systematically registered, as well as AEs and skin lesions appearance. A total of 109 patients (72 CD and 37 UC) contributed 2913 IFX TCs. During a median follow-up of 3.0 [1.5-4.5] years, we observed 684 AEs in 101 patients and 49 skin lesions in 35 patients. There was no significant difference (p = .467) in median TCs between patients with and without skin lesions. However, higher median IFX doses were associated with an increased hazard rate of skin lesions [HR 1.084 (1.024-1.148), p = .005], in addition to female sex [2.210 (1.187-5.310), p = .016] and diagnosis of CD [1.695 (1.241-1.877), p = .011]. Considering IFX therapeutic TC cut-offs of 5.0 and 9.0 µg/mL, there was no significant difference in AE rate (p = .749 and p = .833, respectively). Also, no significant association between IFX doses and AE rate (p = .159). Increasing the IFX dose to achieve therapeutic TCs may not increase the overall risk of AEs in paediatric IBD patients. However, concerns arise regarding the risk of skin lesions, especially in female CD patients.

Application of a Precision-Dosing Model to a Real-World Cohort of Patients on Infliximab Maintenance Therapy: Drug Usage and Cost Analysis.

Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients-56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis-were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 μg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; P = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; P < .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 μg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater.

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.

Correlation between Treatment Outcomes and Serum Vitamin D Levels As Well As Infliximab Trough Concentration among Chinese Patients with Crohn's Disease.

The relationship between vitamin D (vit-D) levels and the effectiveness of infliximab (IFX) in patients with Crohn's disease (CD) remains controversial. To evaluate the interaction between vit-D levels and the response to IFX therapy in patients with CD. This was a retrospective cohort study. Serum vit-D and IFX trough concentrations (TC) were measured in 84 patients, and statistical analyses were performed. The total vit-D deficiency rate at enrollment, at week 14 and week 38, was 64.3%, 41.67%, and 37.5%, respectively (P < 0.001). CD activity index (CDAI) (120, range, 93-142.75) and simplified endoscopic activity score for CD (SES-CD) (2, range, 0-4) at week 14 were lower than that of enrollment (CDAI, 136.5, range, 101.25-196; SES-CD 13, range, 5-23) (P < 0.001). The biochemical remission (BR), clinical remission (CR), endoscopic remission (ER), and response (ERe) rates of week 38 were 76.1%, 88.5%, 22.4%, and 67.2%, respectively. vit-D levels at enrollment were positively correlated with CDAI at week 38 (P = 0.024). IFX serum TC was related to BR (P = 0.036), CR (P = 0.032) at week 14, and ERe (P = 0.009) at week 38. Among Chinese patients with CD, vit-D levels prior to IFX therapy are related to CDAI scores, and IFX serum TC is associated with BR, CR, and ERe.

B-060 Measurement of Infliximab Clearance using a Bayesian Forecasting Tool and Impact of Albumin and Immunization Status During Maintenance Treatment of Inflammatory Bowel Disease

Abstract Background Accelerated Clearance of monoclonal antibodies such as Infliximab (IFX) is a known predictive factor of pharmacokinetic origin that associates with poor outcome in patients with Inflammatory bowel diseases (IBD). We have implemented a Bayesian forecasting tool for IFX (PredictrPK® IFX) and calculated its Clearance. Our objective was to evaluate the impact of Albumin (ALB) and antibodies to IFX (ATI) on Clearance and exposure from patient specimens with IBD and submitted for testing in the routine clinical pharmacokinetic laboratory. Methods IFX concentration and ATI status were determined from serum using a homogenous mobility shift assay. Serum ALB concentration was determined using nephelometry. Clearance was estimated using inputted IFX concentration, ATI status, ALB, dose and interdose interval, and nonlinear mixed effect modeling with Bayesian priors. Patient specimens were collected anytime 20 days after the infusion and submitted for testing. Median Clearance (expressed as L/day) and estimated IFX trough concentrations by ATI status and lower Albumin levels (&amp;lt;4.0 g/dL) was calculated. Statistical analysis consisted of nonparametric Mann-Whitney tests. Results The prevalence of ATI was 9.1% in this cohort of patient specimens. Median Clearance was 0.246 L/day (IQR: 0.191–0.323 L/day) and median IFX Trough concentration was 11.9 µg/mL (IQR: 6.5–19.9 µg/mL). ATI status associated with lower IFX Trough concentrations and higher Clearance (P &amp;lt; 0.01). Lower ALB concentration regardless of ATI status also associated with lower IFX Trough concentrations (P &amp;lt; 0.01). There was twofold higher Clearance and twelvefold lower IFX Trough concentration in the presence of ATI and lower ALB. Results are presented in Table 1. Conclusion The data are consistent with the notion that IFX immunization and lower ALB impact Clearance and exposure to IFX.

Pharmacist-Driven Therapeutic Infliximab Monitoring at the Point of Care Using Rapidly Assessed Drug Levels in Patients with Inflammatory Bowel Disease.

Therapeutic monitoring of infliximab is limited by the time lag between drug-level measurement and dose adjustment, along with the cost of dose escalation. Strategies for dose reduction in stable patients on maintenance infliximab at supratherapeutic levels are uncertain. This study determined the feasibility of a pharmacist-driven strategy for immediate dose adjustment using a sliding scale at the point of care in stable patients with inflammatory bowel disease on maintenance therapy. Adult patients with stable disease undergoing maintenance therapy with infliximab infusions, 5 mg/kg every 8 weeks, were prospectively studied. Trough drug levels were assessed by a rapid assay (and later by ELISA) at all infusions for up to 12 months with immediate but quantitatively small dose adjustment according to a sliding scale targeting a therapeutic range of 3-7 mcg/mL. Disease activity was assessed both clinically and biochemically. The rapid assay and ELISA detected similar infliximab levels, and the strategy added approximately 30 minutes to the duration of infusion events. Only 20% of 48 patients (77% with Crohn disease) had baseline trough infliximab concentrations within the therapeutic range. This value increased 3-fold after 24 and 48 weeks of interventions. One in 2 patients had baseline supratherapeutic levels, and most were brought into the therapeutic range without a discernible impact on disease activity by 1 dose adjustment, but 2 or 3 adjustments were generally needed for 29% of patients with subtherapeutic levels. Overall, drug costs were reduced by 4%. Immediate dose adjustment after infliximab rapid assay performed by a pharmacist using a sliding scale is a feasible strategy. Supratherapeutic infliximab levels can be safely and quickly brought into the therapeutic range using small dose adjustments without affecting disease activity, offsetting (at least partly) costs associated with dose escalation.

P701 A time-to-event model relating infliximab trough concentrations to the risk of relapse after extending the infusion interval

Abstract Background Extending the infliximab infusion interval has been attempted in patients with Crohn’s disease (CD) and ulcerative colitis (UC) who sustained treatment response following an earlier interval shortening. We aimed to identify predictors of sustained remission after infliximab interval extension. Methods: Data from 30 adult patients (17 CD, 13 UC), who underwent infliximab interval extension following earlier interval shortening, were collected from a single-centre database search. All patients were in steroid-free clinical (two-item patient-reported outcome [PRO2] ≤1 [UC] and ≤8 [CD]) and biological (C-reactive protein [CRP] &amp;lt;5 mg/L or faecal calprotectin [FC] &amp;lt;250 mg/kg) remission at interval extension. Time-to-relapse was modelled using a time-to-event (TTE) model with loss of steroid-free clinical and biological remission being the event of interest (NONMEM7.5). Various hazard functions were explored, and disease type, time-varying infliximab concentrations and infliximab clearance were investigated as predictors of the relapse hazard risk. The infliximab clearance was calculated using weighted averaging of the estimates of 18 population pharmacokinetics models.1 Results In total, 37% of patients (n=11) remained relapse-free until one year after infliximab interval extension (Figure 1). A time-constant (exponential) hazard model proved best to describe the relapse data of patients with CD (Figure 2, Table 1). The Gompertz hazard model best described the data of patients with UC, with the relapse hazard risk increasing over time. Patients with CD had an overall higher relapse hazard risk than patients with UC. For patients with UC, the infliximab trough concentration was negatively related to the relapse hazard risk and was included in the model using a sigmoidal inhibitory Emax function. Also, in patients with UC, a higher infliximab clearance was associated with an increase in the relapse risk. The infliximab clearance was also a predictor of the relapse hazard risk, but its effect could not be precisely estimated. Conclusion Patients with CD had a higher relapse risk than patients with UC. Only in patients with UC, the hazard risk increased with time, but this risk was lower when the infliximab trough concentration increased. No exposure-response relationship was observed in patients with CD. Results of this exploratory analysis should be interpreted with care and prospective confirmation is awaited (MODIFI study; NCT04982172).2 1Kantasiripitak W. et al. CPT PSP. 2022 2Sheiner LB. et al. CPT. 1997

P531 A model-based tool for guiding infliximab induction dosing to maximise long-term deep remission in children with inflammatory bowel diseases

Abstract Background Adequate infliximab (IFX) concentrations during induction treatment are predictive for deep remission (corticosteroid-free clinical and endoscopic remission) at six months in children with Crohn’s disease (CD) and ulcerative colitis (UC).1 Under standard IFX induction dosing, children often have low IFX trough concentrations.2 Model-informed precision dosing (MIPD) is advocated as a promising IFX dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric IFX induction treatment. Methods Data from 31 children (4-18 years, 15-76 kg, 20:11 CD:UC) receiving standard IFX induction dosing (5 mg/kg at week [w]0, w2, and w6) were repurposed.1 Eight paediatric population pharmacokinetic models were evaluated (six 2-compartment models and two 1-compartment models). Modelling and simulation were used to identify exposure targets, an optimal sampling strategy, and to develop a multi-model prediction algorithm for implementation into an MIPD software tool.3 A role for IFX clearance monitoring was evaluated. Results A total of 251 IFX concentrations were available (6-10 samples per patient). One patient had undetectable IFX concentrations at w6 and w12 but had no measurable antibodies to IFX (ATI). At six months after start of the IFX treatment, 58% (18/31) of patients achieved deep remission. The measured IFX concentration at w12 was the best predictor and classifier for deep remission. A 7.5 mg/L IFX concentration target at w12 was associated with a 64% probability of deep remission at six months (Figure 1). With standard dosing, less than 80% of simulated children &amp;lt;40 kg attained this target (Figure 2). Immunomodulator combo-therapy only subtly improved probability of target attainment. Presence of ATI lowered the target attainment considerably. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 IFX concentration. The multi-model algorithm outperformed single models when optimising the w6 dose based on combined w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. The predictive performance of the MIPD multi-model algorithm was robust to misspecification of ATI status. IFX clearances at w6 and w12 were predictive for deep remission (P=0.02) (Figure 3). An IFX module was added to the TDMx software tool to facilitate MIPD and clearance monitoring (https://tdmx.shinyapps.io/Infliximab_paediatric/). Conclusion A freely available, interactive, multi-model MIPD software tool is provided to facilitate IFX induction dosing and improve deep remission rates in children with CD and UC. 1van Hoeve et al. J Pediatr 2022. 2van Rheenen et al. J Crohns Colitis 2020. 3Kantasiripitak et al. CPT:PSP 2022.

A Model-Based Tool for Guiding Infliximab Induction Dosing to Maximize Long-term Deep Remission in Children with Inflammatory Bowel Diseases.

Adequate infliximab concentrations during induction treatment are predictive for deep remission [corticosteroid-free clinical and endoscopic remission] at 6 months in children with inflammatory bowel diseases [IBD]. Under standard infliximab induction dosing, children often have low infliximab trough concentrations. Model-informed precision dosing [MIPD; i.e. model-based therapeutic drug monitoring] is advocated as a promising infliximab dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric infliximab induction treatment. Data from 31 children with IBD [4-18 years] receiving standard infliximab induction dosing (5 mg/kg at week [w]0, w2 and w6) were repurposed. Eight paediatric population pharmacokinetic models were evaluated. Modelling and simulation were used to identify exposure targets, identify an optimal sampling strategy, and develop a multi-model prediction algorithm for implementation into an MIPD software tool. A role for infliximab clearance monitoring was evaluated. A 7.5 mg/L infliximab concentration target at w12 was associated with 64% probability of deep remission at 6 months. With standard dosing, less than 80% of simulated children <40 kg attained this target. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 infliximab concentration [rapid assay required]. The multi-model algorithm outperformed single models when optimizing the w6 dose based on both w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. Infliximab clearances at w6 and w12 were predictive for deep remission. A freely available, multi-model MIPD tool facilitates infliximab induction dosing and improves deep remission rates in children with IBD.

Comparison of Short-Term Outcomes for Standard Versus Nonstandard Induction Dosing of Infliximab for Pediatric Inflammatory Bowel Disease.

Recent studies have emphasized the early use of infliximab (IFX) in pediatric patients with inflammatory bowel disease. Standard dosing of 5 mg/kg/dose may not be sufficient to achieve optimal clinical outcomes. The aim of our study was to compare short-term outcomes with standard dosing of IFX to higher, nonstandard dosing of IFX for induction therapy. Retrospective study of 162 pediatric patients receiving either standard (5-6 mg/kg, n = 90) or nonstandard (>6 mg/kg, n = 72) dosing of IFX during induction was performed. Patient demographics, clinical outcomes, and laboratory data were collected. Need for dose escalation during the first 6 months, combination therapy with immunomodulators, and steroid-free progression were investigated. Clinical remission rates between the 2 groups were significantly different, with patients receiving nonstandard dosing demonstrating higher rates (58% vs 78%; p = 0.012). Use of combination therapy with immunomodulators was significantly different between standard and nonstandard groups (80% vs 48%; p < 0.001). Numeric trend in need for IFX dose escalation in the first 6 months was seen between standard and nonstandard groups (54% vs 39%, respectively; p = 0.087). Post-induction IFX trough concentrations, rates of antibody development, drug discontinuation, and infusion reaction were similar. Nonstandard induction dosing of IFX was associated with higher rates of clinical remission, despite similar rates of serum IFX trough concentrations. There was a numeric trend towards the standard group requiring dose escalation within the first 6 months of therapy. Patients given nonstandard dosing may achieve superior clinical outcomes compared with those on standard dosing.

S824 Cost-Effectiveness of Precision-Guided Dosing in Adult Crohn’s Disease Patients Initiating Infliximab Maintenance Therapy

Introduction: Crohn’s disease (CD) patients that lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing provides clinicians with a comprehensive pharmacokinetic (PK) profile that allows for the next biologic dose to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) Precision-guided dosing relative to two IFX dose intensification strategies (DIS). Methods: We developed a hybrid (Markov and decision tree) model of CD patients who had a clinical response to IFX induction and entered IFX maintenance in “remission” or “mild symptoms” health states. The analysis took a US payer perspective, a time horizon of 2 years in the base case, and a cycle length of 4 weeks. There were 3 comparators for IFX dosing: Precision-guided dosing, dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1), and IFX dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab (UST), followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial (PMID: 34978325; 29317275) patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were total discounted costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity and scenario analyses. Results: Total costs and QALYs at 2 years are presented in Table. The ICERs of Precision-guided dosing relative to DIS1 and DIS2 were 171,810 and 127,990, respectively. One-way sensitivity analyses (Figure) demonstrated that the cost-effectiveness of Precision-guided dosing was most sensitive to the time between IFX doses. Precision-guided dosing had the lowest proportion of patients requiring a new biologic through 2 years (0.5% vs 2.4% and 27.7% for DIS1 and DIS2, respectively). Conclusion: Precision-guided dosing provides substantial clinical and QoL benefits for adult CD patients by maintaining clinical remission and avoiding IFX failure; it is cost-effective relative to other DISs at a WTP of $175,000/QALY.Figure 1.: Precision-guided Dosing ICER Relative to DIS2 † Varied by ±10% * Varied by ±5% CD: Crohn's disease, DIS: dose intensification strategy, ICER: incremental cost-effectiveness ratio, IFX: infliximab, M-S: moderate-severe, PMPM: per member per month, Rem: remission Table 1. - Base Case Results (2-year Horizon Discounted) DIS Total QALYs Total Costs ICER Relative to Precision-guided Dosing ICER Relative to DIS1 ICER Relative to DIS2 Incremental NMB vs DIS1 (WTP $150,000/QALY) Incremental NMB vs DIS1 (WTP $50,000/QALY) Incremental NMB vs DIS2 (WTP $150,000/QALY) Incremental NMB vs DIS2 (WTP $50,000/QALY) Precision-guided Dosing* 1.572 $50,753 - 171,810 127,990 -$765 -$4,274 $1,816 -$6,436 DIS1† 1.537 $44,725 171,810 - 95,581 - - $2,581 -$2,162 DIS2 ‡ 1.489 $40,191 127,990 95,581 - -$2,581 $2,162 - - DIS: dose intensification strategy, ICER: incremental cost-effectiveness ratio, NMB: net monetary benefit, QALY: quality-adjusted life year, WTP: willingness to pay.*Model informed precision dosing with homogenous mobility shift assay (Prometheus Laboratories).†Dose intensification based on a combination of symptoms, inflammatory markers and proactive therapeutic drug monitoring. Corresponds to cohorts 1 and 2 of the TAILORIX clinical trial.‡Dose intensification reactive on symptoms only. Corresponds to cohort 3 of the TAILORIX clinical trial.

Cytokine Profile at Diagnosis Affecting Trough Concentration of Infliximab in Pediatric Crohn's Disease.

Background: This study aims to measure the concentration of cytokines produced during the inflammation process to investigate if there are any differences in response to treatment of pediatric Crohn’s disease and to determine if the initial tumor necrosis factor-alpha (TNF-α) level affected the trough concentration of infliximab (IFX). Methods: This study included 30 pediatric patients with moderate-to-severe Crohn’s disease. At the time of diagnosis, blood samples were collected for the measurement of cytokines (IL-6, TNF-α, IL-17A, and IL-10). Blood samples were extracted from patients who had begun IFX treatment to measure the IFX trough concentration immediately before the fourth dose administration. Results: All cytokines (TNF-α, IL-6, IL-10, and IL-17A) were significantly higher in patients who did not achieve clinical or biochemical remission than in those who did (p = 0.027, 0.006, 0.017, 0.032, respectively). TNF-α had a negative correlation with the IFX trough concentration (Pearson coefficient = −0.425, p = 0.034). The diagnostic capability of the initial TNF-α concentration to predict under the therapeutic IFX trough concentration, defined as less than 3 µg/mL, had an area under the receiver operating characteristic of 0.730 (p = 0.049). The TNF-α concentration was set at 27.6 pg/mL as the cutoff value. Conclusions: Measuring cytokines at the time of diagnosis can be used to predict the treatment response. Measuring the initial TNF-α concentration may help to predict the treatment response to IFX. When the initial TNF-α concentration is greater than 27.6 pg/mL, a higher dose of IFX may be more appropriate than routinely administering 5 mg/kg of IFX to maintain the therapeutic concentration.

Rapid infusion of infliximab biosimilars and the incidence and severity of infusion-related reactions in patients with inflammatory bowel disease.

Infliximab is an anti-tumour necrosis factor agent used in the treatment of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. While the use of infliximab is well established in the treatment of IBD, there are now four recently FDA-approved infliximab biosimilars that are increasingly used due to their cost-benefit for patients, institutions and payors. In addition, shortening the length of infliximab infusions from 120 min (standard infusion) to 60 min or less (rapid infusion) has been shown to safely provide further cost-benefit while also improving patient convenience. The safety of rapid infusions has been well-established for the infliximab reference product, however, there are limited data available regarding the safety of rapid infusions for infliximab biosimilars. The purpose of this study was to compare the incidence and severity of infusion reactions among patients with IBD receiving rapid infusion of infliximab reference product compared with infliximab biosimilar. This was a retrospective analysis of electronic health record data of patients with a diagnosis of IBD receiving an infliximab reference product or infliximab biosimilar infusion between December 2020 and December 2021. Patient-level variables included demographics, immunomodulator use, IBD-related hospitalization and infliximab trough concentration and antibody levels. Infusion-related variables of interest included total number of infusions, drug, dose, dosing interval, infusion time and use of pre-medications. Infusion-related reactions were defined as safety concerns documented by the administering nurse (anaphylaxis, shortness of breath, hypotension, swelling, rash, pruritus, hives, flushing, chest pain, muscle pain, joint pain, fevers, chills, headache or hypertension) or administration of emergency medications. Fisher's exact test was used to compare reaction rates. A total of 188 patients met inclusion criteria for analysis, and a total of 1124 infusions were administered during the study period. There were no statistically significant differences among any of the pre-specified outcomes. There were no differences in the incidence of infusion reactions among rapid infusion (60 min) infliximab and infliximab biosimilars (p=0.863). Additionally, there were no differences in the incidence of infusion reactions among standard infusion (120 min) infliximab and infliximab biosimilars (p=0.993). Finally, there were no differences among the rate of infusion reactions between rapid infusion of infliximab biosimilars and standard infusion of infliximab biosimilars (p=0.536). Eight patients experienced safety issues, with three patients requiring emergency medications (1.6% of 188 patients). Rapid infusions of infliximab biosimilars were not associated with an increase in the incidence of infusion reactions compared with: rapid infusion of infliximab reference product, standard infusion of infliximab biosimilars, or standard infusion of infliximab reference product. This should reassure clinicians that rapid infusions of infliximab biosimilars are safe in clinical practice.

Decreased Infliximab Concentrations in Patients With Inflammatory Bowel Disease Who Carry a Variable Number Tandem Repeat Polymorphism in the Neonatal Fc Receptor or Variant HLADQA1*05G>A Genotype.

Multiple variables contribute to variation in patient exposure and response to tumor necrosis factor alpha antagonist biologics such as infliximab. This study aimed to assess the association between maintenance-phase infliximab concentrations and genetic variation in HLADQA1*05G>A and fragment crystallisable (Fc) fragment of IgG receptor and transporter (FCGRT) among patients with inflammatory bowel disease. A cross-sectional study was carried out in participants with inflammatory bowel disease prescribed infliximab who were in the maintenance phase of treatment. Participants were genotyped for the presence of the FCGRT variable number tandem repeat (VNTR) and HLADQA1*05G>A (rs74291249). A point estimate of the infliximab trough concentration during the maintenance phase was determined using a standard enzyme-linked immunosorbent assay for each patient. Other variables associated with infliximab pharmacokinetics were collected. A total of 156 participants with inflammatory bowel disease were included from 2 tertiary care centers affiliated with Western University, London, Canada. Median infliximab trough concentrations were lower in participants who carried the FCGRT VNTR 2/3 or 2/2 (4.14 µg/mL; interquartile range [IQR], 6.48 µg/mL) vs wild type individuals (7.00 µg/mL; IQR, 7.66; P = .0027). Median infliximab trough concentrations were significantly lower in participants who were HLADQA1*05G>A variant carriers (4.73µg/mL; IQR, 4.79) vs wild type individuals (7.85µg/mL; IQR, 7.44; P = .0006). A significant decrease in infliximab trough concentrations was seen in individuals who were dual carriers of variant polymorphisms in HLADQA1*05G>A and FCGRT VNTR (no variants, 8.96µg/mL; IQR, 6.84 vs one variant, 4.96 µg/mL; IQR, 4.95 vs dual variants, 0.86µg/mL; IQR, 5.82). FCGRT VNTR and HLADQA1*05G>A are associated with lower maintenance-phase infliximab concentrations, particularly among patients who carry both variants.