Infliximab Pharmacokinetics Research Articles

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.

P430 The influence of persistent organ damage on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients

Abstract Background Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. Methods The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. Results The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors (Fig. 1). Additionally, alongside FC, both IFX and C-reactive protein demonstrated a significant impact on the temporal aspect of disease progression. Conclusion In this 2-year prospective real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that persistent gut damage, as mirrored by FC, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of the progression of the underlying disease. These findings underscore the imperative need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

P1069 One-year clinical outcomes of switching to subcutaneous infliximab in patients with inflammatory bowel disease on maintenance of intravenous infliximab therapy with or without remission: A multicentre cohort study

Abstract Background An elective switching to the subcutaneous (SC) formulation of infliximab (IFX) has shown effectiveness and safety in patients with inflammatory bowel disease (IBD) on intravenous (IV) IFX maintenance therapy. However, data on long-term outcomes in patients not in clinical remission during maintenance therapy is limited. This study aims to evaluate the long-term outcomes of SC switching in patients who were in clinical remission and not in remission during IV IFX maintenance therapy. Methods This retrospective multicentre study was conducted from January 2021 to October 2023. Clinical remission was defined as Crohn’s Disease Activity Index (CDAI) <150 for Crohn’s disease (CD) and partial Mayo score <2 for ulcerative colitis. Biological remission was defined as faecal calprotectin (FC) <250 µg/g and C-reactive protein (CRP) <0.5 mg/dL. The primary outcome measure was 1-year treatment persistence of SC IFX. Results Among 127 patients included in the study, 80 (62.9%) had CD, and 47 (37.1%) had UC. At the time of switching, 90 patients (70.9 %) were in clinical remission; whereas, 37 (29.1 %) were in a non-remission state. The treatment persistence rate at 1 year was high at 92.9%. Treatment persistence rates between the clinical remission and non-remission groups did not differ significantly (94.4% vs. 89.2%, p=0.287). In both groups, IFX pharmacokinetics and biomarkers between baseline and 12 months (p<0.01) significantly improved. The median infliximab levels increased from a baseline of 3.3 µg/mL (interquartile range [IQR] 1.3–5.1) to 14.4 µg/mL (IQR 9.4–23.0, p<0.001) at 12 months. Disease activity index was stable in the remission group, and decreased in the non-remission group (partial Mayo score, p<0.001; CDAI, p=0.063). At the one-year follow-up, clinical remission and biological remission were achieved in 86.6% and 60.6%, respectively, an increase from baseline (70.9% and 48.0%, respectively). Biologics exposure before IFX was the only significant variable associated with treatment persistence (odds ratio 5.138, 95% confidence interval 1.150–22.951, p=0.032). The concomitant use of immunomodulators was not associated. The incidence of IFX-related adverse events was 14.2%, with only three patients discontinuing treatment. Conclusion Switching to SC IFX from IV IFX maintenance therapy demonstrated high treatment persistence and favourable safety profiles, irrespective of remission status at the time of switching. Patients in both remission or non-remission states showed significant improvement in pharmacokinetics and biomarkers, and/or stable disease activity indices.

The Influence of Subclinical Active Inflammation on IFX Pharmacokinetic Modeling and Disease Progression Assessment: Findings from a Prospective Real-World Study in Inflammatory Bowel Disease Patients.

Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in the majority of its definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Thiopurines have no impact on outcomes of Crohn's disease patients beyond 12 months of maintenance treatment with infliximab

BackgroundThe emergence of new treatments the inflammatory bowel diseases (IBD) raised questions regarding the role of older agents, namely thiopurines. AimsTo clarify the benefits of combination treatment with thiopurines on Crohn's disease (CD) patients in the maintenance phase of infliximab. MethodsIn this analysis of the 2-year prospective multicentric DIRECT study, patients were assessed in terms of clinical activity, faecal calprotectin (FC), C-reactive protein (CRP), and infliximab pharmacokinetics. A composite outcome based on clinical- and drug-related items was used to define treatment failure. ResultsThe study included 172 patients; of these, 35.5 % were treated with combination treatment. Overall, 18 % of patients achieved the composite outcome, without statistically significant differences between patients on monotherapy and on combination treatment (21.6% vs 11.5 %, p = 0.098). Median CRP, FC, and infliximab pharmacokinetic parameters were similar in both groups. However, in the sub-analysis by infliximab treatment duration, in patients treated for less than 12 months, the composite outcome was reached in fewer patients in the combination group than in the monotherapy group (7.1% vs 47.1 %, p = 0.021). ConclusionIn CD patients in maintenance treatment with infliximab, combination treatment does not seem to have benefits over infliximab monotherapy beyond 12 months of treatment duration.

Physiologically-Based Pharmacokinetic Modeling of Anti-Tumor Necrosis Factor Agents for Inflammatory Bowel Disease Patients to Predict the Withdrawal Time in Pregnancy and Vaccine Time in Infants.

Anti-tumor necrosis factor (anti-TNF) agents are widely applied for patients with inflammatory bowel disease (IBD); however, the timing of the last dosing for IBD pregnancy and time to elimination in anti-TNF agent-exposed infants is controversial. This study aimed to determine the optimal timing for the last dosing of anti-TNF agents (infliximab, adalimumab, and golimumab) in pregnant women with IBD, as well as to investigate the recommended vaccine schedules for infants exposed to these drugs. A physiologically-based pharmacokinetic (PBPK) model of anti-TNF agents was built for adults and extrapolated to pregnant patients, fetuses, and infants. The PBPK models successfully predicted and verified the pharmacokinetics (PKs) of infliximab, adalimumab, and golimumab in pregnancy, fetuses, and infants. The predicted PK data were within two-fold of the observed data. The simulated results were used as timing advice. According to the dose of administration, the suggested timing of the last dosing for infliximab, adalimumab, and golimumab is successfully provided based on PBPK predictions. PBPK models indicated that, for infants, the advocated timing of vaccination is 12, 8, and 5 months after birth for infliximab, adalimumab, and golimumab, respectively. Our study illustrated that PBPK models can provide a valuable tool to predict the PKs of large macromolecules in pregnant women, fetuses, and infants, ultimately informing drug-treatment decisions for pregnancy and vaccination regimens for infants.

Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.

The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02ug/mL, P=0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P>0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36ug/mL, P<0.01), 12 (8.94 vs 5.96ug/mL, P=0.02) and 30 (3.89 vs 6.35ug/mL, P=.0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P=0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P=0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P=0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P=0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P<0.05) predicted nonresponse at week 32. Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.

P705 Switching from intravenous to subcutaneous infliximab: clinical and patient experience outcomes

Abstract Background Intravenous (IV) infliximab (IFX) monotherapy is associated with significant loss of response. Therapeutic drug monitoring shows an association with low serum trough drug levels and development of anti-IFX antibodies. Combination therapy with immunomodulators is not always possible, and IFX dose escalation leads to higher drug costs and time pressure on infusion units. Both approaches have raised heightened patient safety concerns due to the Covid-19 pandemic. Subcutaneous (SC) IFX pharmacokinetics lead to improved drug trough levels, which could lead to better clinical outcomes. Methods The NHS Greater Glasgow and Clyde biologics database was used to identify selected patients currently treated with IV IFX for IBD for suitability for SC switch. Patients were contacted to allow informed choice to opt in or out of switch. Baseline clinical data was collected, and patients were reviewed at week 8 and week 24 for assessment of clinical disease activity scores, IFX trough levels/anti-drug antibody levels, and faecal calprotectin. Patient experience outcomes were assessed using a quality of life questionnaire (CUCQ-8). Results 31 patients consented to switch; F:M = 17:14. The majority of patients (16) had Crohn’s disease, with 13 with UC and 2 IBDU. Mean duration of disease was 9.1 years and duration of prior IV therapy was 3.3 years. 28 patients were reviewed at week 8 and 24 at week 24. At week 24, 71% of patients were in clinical remission (Harvey-Bradshaw index score &amp;lt;5 or partial Mayo score &amp;lt;2), 96% had CRP &amp;lt;5 mg/Land 87% had FCP &amp;lt;250µg/g. 21% of patients had subtherapeutic IFX trough levels at baseline, all had increased by week 8 and there were no subtherapeutic levels measured by week 24. One patient had detectable antibodies at week 24, compared with 9 patients at baseline. Three patients required oral steroid therapy during the 24-week follow up period. There were no hospital admissions, significant infections or adverse reactions within the cohort. 15 patients submitted CUCQ-8 scores, of these 7 patients’ scores had worsened at week 8 but by week 24 13/15 were stable or improved compared to baseline. Conclusion Switching from IV to SC infliximab is welcomed by most patients. The efficacy, tolerability, increased drug level and safety which has previously been demonstrated is reproduced in our cohort. This study is the first to explore patient experience outcomes. The finding of initial worsening of the CUCQ-8 score, but overall improvement by week 24 opens further opportunity for engaging patient involvement in switch programmes.

Population Pharmacokinetics of CMAB008 (an Infliximab Biosimilar) and Remicade® in Healthy Subjects and Patients with Moderately to Severely Active Rheumatoid Arthritis.

CMAB008 is a monoclonal antibody developed as a biosimilar to infliximab (Remicade®, Janssen). The pharmacokinetic characteristics of CMAB008 and Remicade® in healthy subjects and patients with moderately to severely active rheumatoid arthritis (RA) were investigated using a population modeling approach, and the pharmacokinetic similarity of CMAB008 to Remicade® was assessed. The population pharmacokinetic model was developed on the basis of intensive pharmacokinetic data from a phase1 study in healthy male subjects and combined intensive and sparse pharmacokinetic data from a phase3 study in patients with RA. A two-compartment model with first-order elimination adequately described CMAB008 and Remicade® concentration data in healthy subjects and patients with RA. The analysis of covariates identified anti-drug antibody (ADA), neutralizing antibody (NAB), real-time body weight (BWT), and real-time albumin (ALB) as significant covariates on clearance, and BWT was also a significant covariate for the central volume of distribution. The treatment type (CMAB008 versus Remicade®) and the study population (healthy subjects versus patients with RA) were not identified as significant covariates on the pharmacokinetics of infliximab, demonstrating pharmacokinetic similarity between CMAB008 and Remicade® in both study populations. The effect of BWT and ALB changes on exposures to infliximab was within the acceptable range, suggesting that the 3mg/kg regimen is appropriate in clinical practice for patients with RA and BTW and ALB distribution within the range evaluated in the current analysis. The pharmacokinetic characteristics were similar between CMAB008 and Remicade® in healthy subjects and patients with RA. CMAB008 can be considered bioequivalent to Remicade®. ClinicalTrials.gov identifiers NCT04779892, NCT03478111.

Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab

Background and AimsThe aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics. MethodsThis was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs). ResultsA total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 108 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 108 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 108 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 108 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts. ConclusionsAchieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.

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.

Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis

We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index), and colectomy-free survival. Thirty-eight participants received IFX (median initial dose, 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P= .013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and 4 (10.8%) participants underwent colectomy by week 26 and 2 years, respectively. Day 3 IFX clearance >0.02 L/h was associated with colectomy (hazard ratio, 58.2; 95% confidence interval, 6.0-568.6; P < .001). At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and at week 26 with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine whether sustained intensification can overcome rapid clearance and improve later outcomes. gov identifier: NCT02799615.

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

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

Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study.

BackgroundIntravenous [IV] infliximab is a well-established therapy for inflammatory bowel diseases [IBD] patients. A subcutaneous [SC] formulation of infliximab [CT-P13] has recently been shown to be as effective as IV infliximab after two doses of IV induction in a randomised trial, but there are no data to support elective switching of patients on maintenance IV infliximab therapy. We aimed to assess the effectiveness of an elective switching programme to SC CT-P13 in patients treated with IV infliximab.MethodsPatients on established maintenance IV infliximab, who switched to SC CT-P13, were included in this retrospective multicentre cohort study. Disease activity was monitored serially with the Harvey-Bradshaw Index [HBI] for Crohn’s disease [CD] and the Simple Clinical Colitis Activity Index [SCCAI] for ulcerative colitis (UC) for up to 12 months at months 3, 6, and 12. Faecal calprotectin [FC] and C-reactive protein [CRP] were recorded at baseline and follow-up, if available. Infliximab trough levels were measured prior to switch and at months 3, 6, and 12 following switch. The primary outcome measure was treatment persistence at latest follow-up. Secondary outcome measures included infliximab pharmacokinetics [PK], safety, need for corticosteroid rescue therapy, and need for surgery.ResultsWe included 181 patients, of whom 115 [63.5%] had CD. The majority [72.4%] were on 8-weekly dosing of intravenous infliximab prior to switching, and more than half [59.1%] were on concomitant immunomodulatory therapy. The majority of patients (CD: 106, 92.2%; UC: 46, 76.7%; and IBD unclassified [IBD-U]: 5, 83.3%) were in clinical remission. Treatment persistence rate was high [n = 167, 92.3%] and only 14 patients [7.7%] stopped treatment during the follow-up period. There was no significant difference between baseline and repeat measurements at 3, 6, or 12 months for HBI, SCCAI, CRP, or FC. Of the total cohort, 25 patients (13.8%) had perianal CD. Of these, only two patients [8%] had worsening of perianal CD and required antibiotic therapy and further examination under anaesthesia [EUA]. Both these patients also switched back to intravenous infliximab. Median infliximab level increased from a baseline of 8.9 µg/dl [range 0.4-16] to 16.0 µg/dl [range 2.3-16, p <0.001] at 3 months. Serum levels stayed stable at 6 months [median 16 µg/dl, range 0.3-17.2] and 12 months [median 16 µg/dl, range 0.3-19.1, both p <0.001 compared with baseline]. Among the variables examined, only antibodies to infliximab [ATI] was associated with infliximab levels (odds ratio [OR] -13.369, 95% CI -15.405, -11.333, p <0.001]. A total of 14 patients [7.7%] developed ATI; of these, nine [64.3%] were on concomitant immunomodulatory therapy. Immunomodulatory therapy was not significantly associated with development of ATI [p = 0.15]. In a subset of patients receiving escalated IV infliximab dosing frequency prior to switching, no difference in treatment persistence was observed in patients receiving weekly versus alternate weekly SC CT-P13. Patient acceptance and satisfaction rates with SC CT-P13 were very high.ConclusionsAmong patients on IV infliximab maintenance therapy switched to SC CT-P13, we observed high treatment persistence rates and low rates of immunogenicity, with no change in clinical disease activity indices or biomarkers. Infliximab levels increased after switch to SC CT-P13, and only ATI was associated with serum infliximab levels. Patient acceptance and satisfaction rates were high with SC CT-P13.

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.

BIOLOGIC PRECISION DOSING IS NOW AVAILABLE AT THE BEDSIDE FOR CHILDREN AND ADULTS WITH INFLAMMATORY BOWEL DISEASE RECEIVING INFLIXIMAB

Abstract INTRODUCTION There is significant variability in infliximab (IFX) pharmacokinetics (PK) in children and adults with multiple population PK models developed and several covariates identified to better predict drug clearance. Fortunately, therapeutic drug monitoring (TDM) is widely available and can be used to simplify model-informed precision dosing. However, empiric (“trial and error”) dose intensifications following TDM to achieve targeted levels can delay obtaining an optimal drug exposure and is a risk for super-therapeutic levels. In this study, we highlight the formal processes to create a clinical decision support tool (CDST) for IFX and assess the physician usability of the novel CDST. METHODS The development team included a PK software consultant, pharmacologists, pediatric gastroenterologists, nurses, software architects, and a human factor engineering firm (Pomiet, Dayton, OH). CDST development occurred in 4 distinct phases (sprints). Design sprints started with structured interviews with key stakeholders and finished with the creation of CDST wireframes (prototypes). Physician usability was assessed with the System Usability Scale (SUS)1 at 3 timepoints. RESULTS CDST design sprints included in-person interviews with 11 unique health care providers (8 physicians) over 26 sessions. During Phase I, clinicians noted current practices and systems to dose optimize biologics are “cumbersome” and “not user-friendly” as key patient data to make informed decisions are in disparate locations within the electronic medical record (EMR). From Phase I to Phase IV, the design team used the wireframes for user feedback, made changes and developed the final CDST, RoadMABTM. Next, information services (IS) personnel integrated the CDST within the EMR. Patient data extraction occurs with a Fast Healthcare Interoperability Resources (FHIR) launch and produces an embedded browser within EMR. Additionally, our team created a standalone replica of the EMR CDST that is secured by Microsoft Azure and hosted by Amazon Web Services. Our precision dosing CDST is supported by PK software that incorporates past IFX administrations and laboratory results (covariates and drug concentrations), conducts Bayesian PK estimation using the selected population PK model and displays the past and predicted concentration-time profiles (Figure 1A). In order to simplify precision dosing during IFX induction, we also created the New Start Wizard within RoadMABTM. Finally, The SUS was administered at three timepoints with a minimum of 2 new physicians at each session. Physician clinical experience is presented in Table1. By the completion of RoadMABTM, the final mean (SD) SUS was 86.5/100 (15.2, Figure 1B). CONCLUSION Our team has created a usable CDST for IFX that is now integrated within the EMR and available as a web portal for bedside (point-of-care) precision dosing.

BIOLOGIC PRECISION DOSING IS NOW AVAILABLE AT THE BEDSIDE FOR CHILDREN AND ADULTS WITH INFLAMMATORY BOWEL DISEASE RECEIVING INFLIXIMAB

There is significant variability in infliximab (IFX) pharmacokinetics (PK) in children and adults with multiple population PK models developed and several covariates identified to better predict drug clearance. Fortunately, therapeutic drug monitoring (TDM) is widely available and can be used to simplify model-informed precision dosing. However, empiric (“trial and error”) dose intensifications following TDM to achieve targeted levels can delay obtaining an optimal drug exposure and is a risk for super-therapeutic levels.

P010 Precision Dosing Tool Forecasts Trough Infliximab and Associates With Disease Status in Inflammatory Bowel Diseases.

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

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment-A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model.

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day−1 and kPint = 0.0079 day−1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

Infliximab Concentrations during Induction Are Predictive for Endoscopic Remission in Pediatric Patients with Inflammatory Bowel Disease under Combination Therapy

To study infliximab (IFX) pharmacokinetics in children with inflammatory bowel disease (IBD) during induction therapy to predict outcome and explore if other covariates influenced outcome. All children with IBD starting IFX therapy (5mg/kg at weeks 0, 2, 6, and 12) for active luminal disease from May 2017 to May 2019 were included and followed prospectively. Patients were sampled at multiple timepoints during induction (trough concentrations and peak concentration at weeks 0, 2, 6, and 12, and intermediate concentration at weeks 1-4). IFX concentrations and cumulative drug exposure were correlated with outcome at 6months. Endoscopic remission was defined as Simple Endoscopic Score for Crohn's Disease of <3 or Mayo endoscopic subscore of 0, and deep remission as endoscopic with clinical remission (Pediatric Ulcerative Colitis Activity Index/Pediatric Crohn's Disease Activity Index of <10). There were 252 serum induction concentrations obtained from 32 patients (81% on concomitant thiopurines). Children in endoscopic remission (all in deep remission) at 6months had significantly higher drug concentrations from week 4 onward. A receiver operating characteristics curve analysis identified IFX trough concentrations at week 12 of ≥5.0μg/mL and area under the curve at weeks 0-12 of ≥4056.0μg∗day/mL as the minimal target to achieve endoscopic remission at 6months (area under the receiver operating characteristics curve, 0.796 [95% CI, 0.62-0.97] and area under the receiver operating characteristics curve, 0.778 [95% CI, 0.61-0.94], respectively). In addition, our findings suggest that proteomic analysis may help to understand IFX response. Higher IFX exposure during induction therapy in pediatric patients with IBD is associated with significantly better endoscopic and deep remission rates at 6months. Drug concentrations differentiate remitters from nonremitters from week 4 after induction onward.