Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials

Fasanmade, Adedigbo A.; Adedokun, Omoniyi J.; Blank, Marion; Zhou, Honghui; Davis, Hugh M.

doi:10.1016/j.clinthera.2011.06.002

Cited by 258 publications

(240 citation statements)

References 40 publications

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“…27 Since only trough concentrations were available, we used a one-compartment model. Because most studies used a 2-compartmental model to describe infliximab pharmacokinetics, [4][5][6][8][9][10]12,13 there is a potential risk of increased bias and decreased precision of PK parameter estimation. However, this limitation was reported for compounds with poorly known pharmacokinetics, which is not the case of infliximab.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the adjustment of dose based on patients' weight, large interindividual variability in infliximab serum concentrations is observed. [1][2][3] Infliximab pharmacokinetics has been analyzed in RA, 4 AS 5,6 and inflammatory bowel disease (IBD) [7][8][9][10][11][12] patients using population compartmental modeling. These studies showed that several individual characteristics such as body weight, [4][5][6]9,10,12,13 sex, 5,9,13 anti-drug antibodies, 14,15 cotreatment with methotrexate 4 or preinfusion C-reactive protein (CRP) 4 were related to infliximab pharmacokinetic parameters.…”

Section: Introductionmentioning

confidence: 99%

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The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Passot

Mulleman

Bejan-Angoulvant

et al. 2016

mAbs

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Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a onecompartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Passot

Mulleman

Bejan-Angoulvant

et al. 2016

mAbs

View full text Add to dashboard Cite

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“…Loss of clinical benefit can be due to an increased clearance of the drug in the presence or absence of anti-drug antibodies (ADAs) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review

et al. 2016

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Background Therapeutic drug monitoring (TDM) of anti-TNF is increasingly used to manage inflammatory bowel diseases (IBD) and rheumatoid arthritis (RA). The costeffectiveness of this strategy is debated. Methods All studies comparing the cost-effectiveness of a TDM-based strategy and an empirical dose management of anti-TNF in IBD or RA were screened. Studies were identified through the MEDLINE electronic database (up to July 2016), and annual international meeting abstracts were also manually reviewed. Results Seven studies were included: two randomized controlled trials (RCTs) enrolling 332 patients [247 Crohn's disease (CD) and 85 ulcerative colitis (UC)] and five modeling approaches. Four studies included only CD patients, one included both CD and UC patients, and two included only RA patients. Three studies compared the cost-effectiveness of the two strategies in patients with secondary infliximab (IFX) failure (dose-escalation strategy), one in patients in remission on optimized IFX (deescalation strategy), one in patients starting adalimumab, and two in patients with clinical response to maintenance anti-TNF therapy. The two RCTs demonstrated that a TDM strategy led to major cost savings, ranging from 28 to 34 %. The three modeling approaches with regard to CD patients demonstrated cost savings ranging from $5396 over a 1-year period to €13,130 per patient at 5 years of follow-up. A TDM strategy also led to major cost savings in the two modeling approaches in RA patients. Conclusions Available evidence indicates that a TDM strategy leads to major cost savings related to anti-TNF therapy in both IBD and RA patients, with no negative impact on efficacy.

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“…1), particularly in pediatric patients (5,6) because the relationship between drug clearance and weight (if it exists) is rarely linear or simple (7). This finding has been confirmed for many compounds, including infliximab (8,9). The US FDA produced a guidance document on dose selection for FTIH studies (10) suggesting initial dose selection based on bodyweight (e.g., mg/kg) to scale exposure seen in nonclinical studies to safe levels in humans.…”

Section: Adjustment For Body Sizementioning

confidence: 90%

Dashboard Systems: Implementing Pharmacometrics from Bench to Bedside

Mould

Upton

Wojciechowski

2014

AAPS J

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Abstract. In recent years, there has been increasing interest in the development of medical decisionsupport tools, including dashboard systems. Dashboard systems are software packages that integrate information and calculations about therapeutics from multiple components into a single interface for use in the clinical environment. Given the high cost of medical care, and the increasing need to demonstrate positive clinical outcomes for reimbursement, dashboard systems may become an important tool for improving patient outcome, improving clinical efficiency and containing healthcare costs. Similarly the costs associated with drug development are also rising. The use of model-based drug development (MBDD) has been proposed as a tool to streamline this process, facilitating the selection of appropriate doses and making informed go/no-go decisions. However, complete implementation of MBDD has not always been successful owing to a variety of factors, including the resources required to provide timely modeling and simulation updates. The application of dashboard systems in drug development reduces the resource requirement and may expedite updating models as new data are collected, allowing modeling results to be available in a timely fashion. In this paper, we present some background information on dashboard systems and propose the use of these systems both in the clinic and during drug development.

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Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials

Cited by 258 publications

References 40 publications

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review

Dashboard Systems: Implementing Pharmacometrics from Bench to Bedside

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