Mo1857 - Vedolizumab Levels During Induction are Associated with Long-Term Clinical and Endoscopic Remission in Patients with Inflammatory Bowel Disease

Abstract Background Although higher infliximab (IFX) trough levels (TL) have been associated with better outcomes, the ideal predictive sampling time and cut-points to achieve endoscopic remission remain unclear in children with inflammatory bowel disease (IBD). Therefore, we evaluated the pharmacokinetics of IFX during induction to predict long-term outcome of IFX. Methods All children with Crohn’s disease (CD) or ulcerative colitis (UC) starting IFX therapy (5 mg/kg at weeks 0–2–6–12) for active luminal disease from May 2017 till May 2019 were followed prospectively. IFX levels were measured by Ridascreen IFX Monitoring ELISA (TL at weeks 2–6–12, peak at weeks 0–2–6 and intermediate at weeks 1–4). IFX levels and cumulative drug exposure (area under the curve (AUC) till week 12) were correlated with the outcome at month 6. Clinical remission was defined as PUCAI/PCDAI <10, biochemical remission as CRP ≤5 mg/l + ESR ≤20 mm/h, endoscopic remission as SES-CD <3 or Mayo endoscopic sub-score = 0 and deep remission if both clinical + endoscopic remission. Results were analysed using Mann–Whitney U-test (presented as median [IQR]). Results A total of 252 serum induction levels were included from 32 patients (20 CD and 12 UC; 38% male; median age at start of IFX 13.8 years [11.3–14.9]; 84% on concomitant thiopurines). Clinical remission was achieved in 24 (75%) patients and 18 (56%) were in endoscopic remission (all in deep remission) at month 6. Endoscopic remission at month 6 was associated with significantly higher median IFX TL at week 4 (38.8 µg/ml [24.3–46.0] vs. 23.5 µg/ml [10.5–36.6], p = 0.017), at week 6 (19.9 µg/ml [10.1–26.3] vs. 11.1 µg/ml [3.7–19.9], p = 0.031), at week 12 (9.6 µg/ml [5.5–11.9] vs. 3.5 µg/ml [2.7–7.2], p = 0.004; fig1.) and higher AUC week 0–12 (4574.7 µg*day/ml [3783.0–5160.8] vs. 3722.9 µg*day/ml [3102.2–3991.9], p = 0.008). Median IFX TL at week 12 were significantly higher in children with clinical remission (8.6 µg/ml [5.1–12.0] vs. 4.3 µg/ml [3.1–5.9], p = 0.033), but not for biological remission (6.7 µg/ml [4.0–12.0] vs. 4.3 µg/ml [1.2–7.2], p = 0.250; Figure 2) at month 6. ROC analysis identified an IFX TL at week 12 ≥ 5.0 µg/ml and an AUC weeks 0–12 ≥ 4056.0 µg*day/ml as minimal target to achieve endoscopic remission at mo. 6 (AUROC: 0.796 [95% CI: 0.62–0.97] and AUROC: 0.778 [95% CI: 0.61–0.94], respectively; Figure 3.). Height, haemoglobin and PCDAI score at start of IFX therapy, significantly correlated with week 12 IFX TL. Conclusion Adequate IFX exposure during induction in paediatric IBD patients is associated with significantly better clinical, endoscopic and deep remission rates at month 6. Model-informed precision dosing can assist physicians to achieve optimal exposure during induction more precisely (and rapidly) what is essential for an optimal outcome.

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Faculty Opinions recommendation of Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1165801.628867 ◽

2009 ◽

Author(s):

Ian Beales

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Efficacy And Safety ◽

Term Efficacy ◽

Inflammatory Bowel

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Novel Targets For Therapeutic Intervention in Inflammatory Bowel Disease. What is the Best Way to Assess the Safety Profile of a Drug?

Current Pharmaceutical Design ◽

10.2174/1381612825666190308102021 ◽

2019 ◽

Vol 25 (1) ◽

pp. 57-63 ◽

Cited By ~ 2

Author(s):

Clara Yzet ◽

Stacy S. Tse ◽

Maia Kayal ◽

Robert Hirten ◽

Jean-Frédéric Colombel

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Evaluation Process ◽

Population Based ◽

Stage Of Development ◽

Remission Rates ◽

Safety Parameters ◽

Post Marketing ◽

Inflammatory Bowel

The emergence of biologic therapies has revolutionized the management of inflammatory bowel disease (IBD) by halting disease progression, increasing remission rates and improving long-term clinical outcomes. Despite these well-described benefits, many patients are reluctant to commence therapy due to drug safety concerns. Adverse events can be detected at each stage of drug development and during the post-marketing period. In this article, we review how to best assess the safety parameters of new IBD medications, from the earliest stage of development to population-based registries, with a focus on the special populations often excluded from the evaluation process.

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Long-Term Effectiveness of Oral Ferric Maltol vs Intravenous Ferric Carboxymaltose for the Treatment of Iron-Deficiency Anemia in Patients With Inflammatory Bowel Disease: A Randomized Controlled Noninferiority Trial

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab073 ◽

2021 ◽

Author(s):

Stefanie Howaldt ◽

Eugeni Domènech ◽

Nicholas Martinez ◽

Carsten Schmidt ◽

Bernd Bokemeyer

Keyword(s):

Inflammatory Bowel Disease ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Primary Endpoint ◽

Bowel Disease ◽

Deficiency Anemia ◽

Ferric Carboxymaltose ◽

Inflammatory Bowel ◽

Intent To Treat

Abstract Background Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. Methods In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center’s standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. Results For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. Conclusions Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated.

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