Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis

Adedokun, Omoniyi J.; Sandborn, William J.; Feagan, Brian G.; Rutgeerts, Paul; Xu, Zhenhua; Marano, Colleen; Johanns, Jewel; Zhou, Honghui; Davis, Hugh M.; Cornillie, Freddy; Reinisch, Walter

doi:10.1053/j.gastro.2014.08.035

Cited by 290 publications

(243 citation statements)

References 27 publications

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“…It is known that the bio-availability of ciclosporin is short-lived after cessation of treatment, whereas bio-availability of infliximab, although varying from subject to subject, can persist up to 6 months after the last infusion. 105 Therefore, with the exception of malignancy, we considered that relatedness would be unlikely if the event occurred more than 1 month after cessation of treatment with ciclosporin, but could be related up to 6 months after infliximab. These principles were agreed with the Clinical Trials Unit and the DMEC before we undertook the review.…”

Section: Strengths and Weaknesses Of The Studymentioning

confidence: 99%

“…As far as I can remember it took a while for that patient to settle down with his bowels ...day 3 they still feel bas they still feel worse (102,105) HPN25b the patients that have been using it seem to have responded really well I've not seen anybody that's had to go onto you know to anything else having had ciclosporin everyone that I've seen using it have responded well. (74) HP3 sensible and good experience of this drug 'when it works it is fantastic' (23-25) HP3 'labouring work' but works well (25) HP7 data suggests it is effective, easier to administer, simpler regime, less palava (28) HP11 this is the one thing I don't like about inflix because there is no data to give us a clear timescale or timeline for decision making (94) HP12 the other slight issue with inflix is the speed of response (39) HP12 the response is slightly sort of slower (45) HP12 sometimes it is a bit challenging that you have given the inflix if they are going to take a sort of week to 10 days time, would you hold the nerve (47) HP12 it's at least as effective as ciclosporin with the additional benefit of convenience and potentially less toxic (222) HP16 it's very clear to me it's a very effective treatment for a proportion of patients with really severe colitis and there's no doubt that we've had some patients with toxic dialation, who've really been at the far end of the spectrum who have responded perfectly immediately (215) HP16 I think that the efficacy is best...at worst is broadly similar (409) DOI: 10.3310/hta20440 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL.…”

Section: Excellentmentioning

confidence: 99%

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Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Williams

Alam

Alrubaiy

et al. 2016

Health Technol Assess

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BackgroundThe efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness.ObjectiveTo compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC.MethodBetween May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohn’s and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1–3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years.ResultsThe 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouring ciclosporin, 95% confidence interval (CI) –0.0088 to 0.0682;p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouring ciclosporin, 95% CI –0.032 to 0.096;p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouring ciclosporin, 95% CI –0.0250 to 0.0353;p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188;p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouring ciclosporin, 95% CI 0.590 to 1.493;p = 0.788); participants with serious adverse reactions (OR 0.660 favouring ciclosporin, 95% CI 0.282 to 1.546;p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917;p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114;p = 0.998); deaths (all three who died received infliximab;p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference –£5632, 95% CI –£8305 to –£2773;p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin.ConclusionsTotal cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1–3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin.Trial registrationCurrent Controlled Trials ISRCTN22663589.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 44. See the NIHR Journals Library website for further project information.

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Section: Strengths and Weaknesses Of The Studymentioning

confidence: 99%

Section: Excellentmentioning

confidence: 99%

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Williams

Alam

Alrubaiy

et al. 2016

Health Technol Assess

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“…Regarding UC patients, these proportions would be 41%, 57% and 67% for a target concentration of 3.7 mg/L. 24 …”

Section: Final Model With Covariatesmentioning

confidence: 99%

“…The data set was simulated 1000 times. The 90% confidence interval of simulated steady-state infliximab trough concentrations at 22 weeks was compared to infliximab trough concentrations predictive of good clinical response in RA (2.5 mg/L, 22 ), Crohn's disease (3.5 mg/L, 23 ) and ulcerative colitis (3.7 mg/L, 24 ). …”

Section: Simulation Processmentioning

confidence: 99%

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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“…Cohort studies and post hoc analyses show that serum IFX trough concentrations (TC) correlate with clinical response, clinical remission, and mucosal healing in patients with IBD [8][9][10][11].…”

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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Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis

Cited by 290 publications

References 27 publications

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

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

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