99 research outputs found
The effect of aging on infliximab exposure and response in patients with inflammatory bowel diseases
No full textAIMS: Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety. METHODS: Retrospective case-control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time-to-event models were developed to describe the hazard of safety events over time. RESULTS: A total of 104 patients (46 elderly, ≥65 years) were included. A two-compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat-free mass, lower C-reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age. CONCLUSIONS: Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure.sponsorship: Ann Gils received a TBM grant of the Research Foundation - Flanders (FWO), Belgium, Grant/Award Number: T003716N; Erwin Dreesen is a postdoctoral research fellow of the Research Foundation - Flanders (FWO), Belgium, Grant/Award Number: 12X9420N; Marc Ferrante is a senior clinical investigators of the Research Foundation -Flanders (FWO), Belgium; Severine Vermeire is a senior clinical investigators of the Research Foundation Flanders (FWO), Belgium (Research Foundation - Flanders (FWO), Belgium|T003716N, 12X9420N)status: Publishe
Pharmacodynamic Monitoring of Biological Therapies in Chronic Inflammatory Diseases
No full textBACKGROUND: Psoriasis, psoriatic arthritis, spondyloarthritis, rheumatoid arthritis, ulcerative colitis, and Crohn disease share similar underlying pathophysiological processes, providing the opportunity to treat the patients using similar biological therapies. Failure of biological treatments due to underexposure can be managed by therapeutic drug monitoring. Adjusting the treatment based on pharmacokinetic monitoring can be further improved by taking pharmacodynamic parameters such as clinical and molecular markers into account. METHODS: Here, we critically evaluate the existing evidence, the hurdles to be taken, and the opportunities for a widespread implementation of pharmacodynamic monitoring. RESULTS: Pharmacodynamic monitoring typically is the monitoring of biochemical markers. A pharmacodynamic marker preferably is specific for the pharmacological action of a drug, but most of the time nonspecific pharmacodynamic markers are used, such as C-reactive protein and the erythrocyte sedimentation rate. Clinical pharmacodynamic markers typically evaluate physical variables or symptoms. Although physician-reported outcomes have been studied for a longer time and often have been shown to correlate well with molecular pharmacodynamic markers and treatment outcomes, the introduction of mobile health or mHealth technologies caused a shift toward patient-reported outcomes, with the associated challenge to consistently reflect the inflammatory state, thereby preventing undertreatment or unnecessary overdosing of patients. CONCLUSIONS: The primary goal of pharmacodynamic monitoring is to optimize the response, but it can also have an impact on safety, costs, patient adherence, etc. Ideally, the constant remote monitoring of patient-reported disease activity is expected to become the standard, facilitated by mHealth technologies.sponsorship: A. Gils: lecture fees from MSD, Janssen Biologicals, Pfizer, Takeda, Abbvie, Novartis; Advisory board: Takeda; Financial research support: Pfizer, MSD, Takeda; License agreement: R-biopharm, apDia, Merck. The remaining author declares no conflict of interest. (Pfizer, MSD, Takeda)status: Publishe
Development of a population pharmacokinetic and pharmacodynamic model to describe the effect of infliximab induction therapy on mucosal healing in patients with ulcerative colitis
No full textInfliximab (IFX) is a chimeric monoclonal antibody that neutralizes the pro-inflammatory cytokine tumour necrosis factor alpha. Intravenous administration of IFX following an induction scheme of 5 mg/kg body weight at days 0, 14 and 42 has been shown to induce mucosal healing (MH) in 61% of patients with ulcerative colitis at day 56[1]. A positive association between IFX serum concentrations during induction therapy and post-induction MH (between day 56 and 98) has been reported[2,3].
In this study, we applied nonlinear mixed effects methodology to compare potential exposure targets for prediction of MH.status: Publishe
Blocking the 47 integrin through vedolizumab: Necessary but not sufficient?
No full textno abstract availablesponsorship: This work was supported by the Fund for Scientific Research Flanders [grant numbers G.0617.12 and TBM T003716N]. (Fund for Scientific Research Flanders|G.0617.12, Fund for Scientific Research Flanders|TBM T003716N)status: Publishe
Letter: overcoming secondary loss of response to infliximab-it is not the drug, it is how you use it! Authors' reply
No full textstatus: Publishe
Therapeutic drug monitoring of anti-tumor necrosis factor agents : lessons learned and remaining issues
No full textTherapeutic drug monitoring (TDM) of anti-tumor necrosis factor agents (anti-TNFs) has received extensive attention due to its potential for improving treatment outcomes in patients with inflammatory bowel diseases. However, the benefits of applying TDM in clinical practice remain largely unclear due to a lack of evidence from the available prospective randomized controlled studies. The questionable evidence for TDM obtained in these studies can be caused by several design suboptimalities, including long turnaround times of sample analysis, use of inappropriate exposure targets, insufficiently precise algorithms for dose optimization, and inapt trial designs. In future studies, model-informed precision dosing in combination with rapid testing methods is recommended to maximize the potential of TDM of anti-TNFs.sponsorship: ED is a postdoctoral research fellow of the Research Foundation - Flanders (FWO), Belgium (grant number 12X9420N). (Research Foundation - Flanders (FWO), Belgium|12X9420N)status: Publishe
Monitoring a Combination of Calprotectin and Infliximab Identifies Patients With Mucosal Healing of Crohn's Disease Reply
No full textsponsorship: The work was supported by a TBM grant T003716N from the Research Foundation, Flanders, Belgium. (TBM grant from the Research Foundation, Flanders, Belgium|T003716N)status: Publishe
Corrigendum to “itraconazole for COVID-19: Preclinical studies and a proof-of-concept randomized clinical trial Laurens”
No full textsponsorship: This project has received funding from the Covid19-Fund KU Leuven/University Hospitals Leuven, the COVID-19 call of the Research Foundation-Flanders (FWO) (grant G0G4820N) , the European Union's Horizon 2020 research and innovation program (Grant 101,003,627, Swift COronavirus therapeutics REsponse project) and the Bill and Melinda Gates Foundation (Grant INV00,636) . LLi is member of the Institute of Tropical Medicine's Out-break Research Team which is financially supported by the Department of Economy, Science and Innovation (EWI) of the Flemish government. BV is supported by a research grant of the Frans Van de Werf Fund for Clinical Cardiovascular Research. P. Verhamme, TV, P. Vermeersch are senior clinical investigators of the FWO. We thank Johnson & Johnson for determining drug concentrations in hamster samples and for providing. guidance on the dosing. We thank Lindsey Bervoets, Carolien De Keyzer, Elke Maas and Jasper Rymentants for the technical support with the animal experiments.TNDD is funded by the Horizon 2020 grant OrganoVIR 812,673 on the project 'Organoids for Virus Research-An innovative training-ITN programme'. XW and XZ received funding of the China Scholarship Council (CSC) (grant number 201,806,170,087 and 201,906,170,033) . Part of this research work was performed using the 'CapsIt' research infrastructure (project ZW13-02) that was financially supported by the Hercules Foundation (FWO) and Rega Foundation, KU Leuven. (Covid19-Fund KU Leuven/University Hospitals Leuven, Research Foundation-Flanders (FWO)|G0G4820N, European Union|101,003,627, Bill and Melinda Gates Foundation|INV00,636, Department of Economy, Science and Innovation (EWI) of the Flemish government, Frans Van de Werf Fund for Clinical Cardiovascular Research, Horizon 2020 grant|OrganoVIR 812,673, China Scholarship Council (CSC)|201,806,170,087, China Scholarship Council (CSC)|201,906,170,033, Hercules Foundation (FWO)|ZW13-02, Rega Foundation, KU Leuven|ZW13-02)status: Publishe
Benefits of TDM in clinical management: a test case in infliximab for ulcerative colitis
No full textInfliximab (IFX) is used in patients with ulcerative colitis (UC) to achieve mucosal healing (MH, defined as Mayo endoscopic sub-score <= 1). A pharmacokinetic/pharmacodynamic (PKPD) model was established [1] linking IFX exposure to probability of mucosal healing (pMH), based on a previously published dataset [2]. The model allows to optimize dosing to increase population exposures, which is predicted to improve clinical outcomes. Compared to open loop dosing, therapeutic drug monitoring (TDM) may be used to optimize dosing even further.status: Publishe
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