Primary and secondary nonresponse to infliximab: mechanisms and countermeasures

Wong, Uni; Cross, Raymond K.

doi:10.1080/17425255.2017.1377180

Cited by 66 publications

(49 citation statements)

References 59 publications

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“…There were no significant safety concerns in this study regarding the development of anti‐drug antibodies to IFX or the occurrence of IFX infusion reactions. The rate of discontinuation of IFX in this study was 6.5% which is higher than the 2% reported in the TAXIT study; however, in the TAXIT study, patients were already in a stable state on maintenance therapy whereas our study included patients who were undergoing induction therapy, and from previous studies, we know that primary non‐response occurs to anti‐TNF therapy in up to 40% of patients in clinical trials and up to 20% in clinical series …”

Section: Discussioncontrasting

confidence: 67%

The effects of proactive therapeutic drug monitoring vs reactive therapeutic drug monitoring in a virtual biologic clinic, a retrospective cohort study

et al. 2019

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Summary Background Proactive therapeutic drug monitoring (proactive‐TDM) to optimise maintenance infliximab (IFX) trough levels prior to loss of response reduces the risk of treatment failure, inflammatory bowel disease (IBD)‐related surgery and hospitalisation when compared with reactive monitoring (reactive‐TDM). Aim The aim of this study is to investigate if proactive‐TDM in a virtual biologic clinic (VBC) improves patient disease control determined by number of hospital admissions, surgeries, patient reported outcome measures (PROMs) and biomarkers of disease activity. Methods We conducted a single‐centre retrospective observational study. Data were collected from commencement of the VBC in June 2016 to September 2017. All IBD patients on IFX in the VBC were included. PROMs were recorded using the IBD‐Control‐8 sub‐score and Visual Analogue Scale. Results One hundred and twenty‐three patients were included in the study. A statistically significant improvement in faecal calprotectin was observed with proactive‐TDM with a P‐value <.001. There was a 59% reduction in crisis IBD admissions with the introduction of proactive‐TDM in the VBC (P‐value <.005). Dose de‐escalations in the first 3 months of the VBC lead to cost savings of €32 000 per annum. Conclusions The introduction of proactive‐TDM resulted in a significant reduction in hospital admissions, an increase in mean IFX trough levels, a significant improvement in faecal calprotectin and adjustment to therapy in 33% of patients. Proactive‐TDM in the setting of a VBC is a method of managing IBD patients on IFX therapy with the potential for significant cost savings.

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Section: Discussioncontrasting

confidence: 67%

The effects of proactive therapeutic drug monitoring vs reactive therapeutic drug monitoring in a virtual biologic clinic, a retrospective cohort study

et al. 2019

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“…The main risk factors for primary nonresponse to IFX are male sex, high body mass index, high CRP and FC, high TNF level, high IL-8 level, high TNF/CRP ratio, low serum albumin, complicated CD, deep ulcerations on endoscopy, smoking, small bowel involvement, disease duration greater than 2 years, FAS-L mutation, caspase-9 mutation, and high oncostatin M expression [12,[27][28][29][30][31][32]. In addition to the above, the pharmacokinetics and pharmacodynamics of biological therapy should be considered to optimize biological therapy with anti-TNF drugs [28].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, approximately 30-40% of patients lose response during the first year of maintenance therapy (secondary loss of response) or might be intolerant to anti-TNFs [10,11]. Clinical and analytical factors have also been associated with primary nonresponse: smoking, long disease duration, older age, previous surgery, complicated phenotype and prior failure of another anti-TNF-α; and laboratory factors related to active gut inflammation, such as C-reactive protein (CRP), and nutritional factors such as serum albumin levels [12][13][14]. Pharmacokinetic processes play a key role in primary nonresponse and the loss of response [15].…”

Section: Introductionmentioning

confidence: 99%

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Beltrán

Iborra

Saéz-González

et al. 2018

Dig Dis

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Introduction: The association between infliximab (IFX) and fecal calprotectin (FC) levels on one hand, and the clinical and endoscopic response of patients with inflammatory bowel disease on the other, is well established. Objective and Methods: To investigate the association between inflammatory biochemical parameters and serum concentrations of IFX during induction treatment with a primary nonresponse in a prospective cohort of Crohn’s disease (CD) patients. Results: Of the 35 patients included, 8 (22.8%) had primary nonresponse at the end of induction. Induction IFX levels were lower among primary nonresponders at weeks 6 and 14 (week 6: median IFX level 7.3 vs. 11.2 μg/mL, respectively, p = 0.090; week 14: median IFX level 1.5 vs. 4.7 μg/mL, respectively, p = 0.020). FC levels were higher in patients with primary nonresponse versus primary response at weeks 0, 6, and 14 (week 0: median FC level 1,830 vs. 410 μg/g, respectively, p = 0.030; week 6: median FC level 1,150 vs. 230 μg/g, respectively, p = 0.074; week 14: median FC level 1,210 vs. 208 μg/g, respectively, p = 0.060). For the multivariate analysis, the median IFX level at week 14 and median FC level at week 0 were independently associated with primary nonresponse. A significant inverse correlation was determined between FC level at week 0 and IFX level at week 14 (Spearman’s rho correlation, 0.440; p < 0.05). Conclusions: IFX levels (at week 14) and baseline FC levels could predict primary nonresponse after induction IFX therapy in patients with CD. A high baseline inflammatory load might modify the pharmacokinetic processes of anti-tumor necrosis factor drugs. Drug level monitoring and measurement of baseline inflammatory parameters could improve the efficacy of IFX in the induction therapy of patients with active CD.

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“…Other variables that are being considered in present research on mAb/Fc immunogenicity include the change in ADA rate over time, 28 the effect of other drug therapy taken with the mAb/Fc product, 29 and the effect dose and drug concentration management. 30 As mentioned above, in January 2019 the FDA released a new Guidance for Industry: Immunogenicity Testing of Therapeutic Protein Products-Developing and Validating Assays for Anti-Drug Antibody Detection. 2…”

Section: Immunogenicitymentioning

confidence: 99%

Monoclonal Antibodies and Fc‐Fusion Proteins for Pediatric Use: Dosing, Immunogenicity, and Modeling and Simulation in Data Submitted to the US Food and Drug Administration

Liu

Dallmann

Wang

et al. 2019

The Journal of Clinical Pharma

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The experience with the use of monoclonal antibodies and Fc‐fusion proteins (mAb/Fc) in the pediatric population is limited. The objective of this study is to review those factors impacting the clinical efficacy and product safety of mAb/Fc products in pediatric patients during drug development. We reviewed the list of biologic products in the US Food and Drug Administration's Purple Book as of March 2018 with a focus on mAb/Fc products that are indicated for use in both adults and pediatric patients. Of 68 mAb/Fc products in the Purple Book (excluding biosimilars), 20 products have approved indications in both adults and children. Thirteen products had concurrent approval for both adult and pediatric populations. The sample size of pediatric studies generally ranged from approximately 2% to 70% of the sample size of adult studies with the same indication. In general, pediatric dosing regimens were found to be more based on body weight and weight tiered than the regimens for adults. Modeling and simulation techniques comprised mainly population pharmacokinetic and pharmacodynamic models. A review of the immunogenicity incidence did not reveal any notable difference in the 5 products having data on both pediatric and adult patients. In conclusion, most of the mAb/Fc products have a different weight‐based dosing regimen for pediatric patients versus adults. An understanding of the comparative experience in drug development for mAb/Fc products between adult and pediatric patients coupled with the application of advanced modeling and simulation methods should assist future development of new mAb/Fc products for pediatric patients.

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Primary and secondary nonresponse to infliximab: mechanisms and countermeasures

Cited by 66 publications

References 59 publications

The effects of proactive therapeutic drug monitoring vs reactive therapeutic drug monitoring in a virtual biologic clinic, a retrospective cohort study

The effects of proactive therapeutic drug monitoring vs reactive therapeutic drug monitoring in a virtual biologic clinic, a retrospective cohort study

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Monoclonal Antibodies and Fc‐Fusion Proteins for Pediatric Use: Dosing, Immunogenicity, and Modeling and Simulation in Data Submitted to the US Food and Drug Administration

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