Association Between Low Trough Levels of Vedolizumab During Induction Therapy for Inflammatory Bowel Diseases and Need for Additional Doses Within 6 Months

Williet, Nicolas; Boschetti, Gilles; Fovet, Marion; Bernado, Thomas Di; Claudez, Pierre; Tedesco, Émilie Del; Jarlot, Camille; Rinaldi, Leslie; Berger, Anne‐Emmanuelle; Phélip, Jean-Marc; Flourié, Bernard; Nancey, Stéphane; Paul, Stéphane; Roblin, Xavier

doi:10.1016/j.cgh.2016.11.023

Cited by 108 publications

(122 citation statements)

References 10 publications

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“…In that study, in which rates of mucosal healing improved with increasing vedolizumab concentration quartiles, the highest vedolizumab concentration quartile at week 6 corresponded to a concentration of >35.7 μg/mL. In contrast, a study by Williet et al reported that vedolizumab trough concentrations of <18.5 µg/mL at week 6 were associated with a need for drug optimisation within 6 months, with an AUROC of 72% . However, that study differed from the present analysis in a number of ways: the Williet et al study was rather small, with only 47 patients in total; two‐thirds of the patients in that study had CD, which may be important because the observed vedolizumab dose‐response relationship was less consistent in GEMINI 2 (CD) compared with GEMINI 1 (UC); and that study did not adjust for factors known to affect vedolizumab clearance.…”

Section: Discussioncontrasting

confidence: 71%

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation

Osterman

Rosario

Lasch

et al. 2019

Aliment Pharmacol Ther

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Summary Background Prospectively designed studies assessing the exposure‐response profile of vedolizumab are lacking. Observational exposure‐response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance. Aims To (a) investigate the vedolizumab exposure‐response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short‐ and long‐term clinical outcomes in adults with ulcerative colitis in GEMINI 1. Methods Propensity‐score‐based case‐matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti‐tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated. Results Among 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 µg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52. Conclusions In this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short‐ and long‐term remission. Potential induction and maintenance target concentrations were proposed for further study.

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Section: Discussioncontrasting

confidence: 71%

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation

Osterman

Rosario

Lasch

et al. 2019

Aliment Pharmacol Ther

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“…These AVA disappeared over time, confirming that antibodies to vedolizumab are transient . Multiple studies have reported low immunogenicity of vedolizumab with AVA development rates ranging from 0.0% to 4.1%, most of these using a drug‐sensitive assay . In our study, the immunogenicity rate is higher, most likely due to the sole inclusion of patients who discontinued vedolizumab therapy and the drug‐tolerant nature of the assay.…”

Section: Discussionmentioning

confidence: 94%

“…Antidrug antibodies are frequently underestimated because most of the commonly used assays are not drug‐tolerant and are unable to detect antidrug antibodies in the presence of drug. Consequently, the 4% antidrug antibody positivity during vedolizumab treatment observed in the GEMINI trials might be an underestimation …”

Section: Introductionmentioning

confidence: 99%

Immunogenicity is not the driving force of treatment failure in vedolizumab‐treated inflammatory bowel disease patients

Berghe

Verstockt

Tops

et al. 2019

J of Gastro and Hepatol

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Background and Aim The pivotal GEMINI trials reported low immunogenicity of vedolizumab. However, anti‐vedolizumab antibodies (AVA) are frequently underestimated because most assays are not drug‐tolerant and unable to detect antidrug antibodies while there is drug in the circulation. This study aimed to explore which antidrug antibody assay is best suited to detect AVA and investigated immunogenicity of vedolizumab in inflammatory bowel disease (IBD) patients discontinuing vedolizumab therapy. Methods A drug‐tolerant affinity capture elution (ACE) assay was developed for the measurement of AVA in the presence of vedolizumab and compared with the previously established drug‐resistant and drug‐sensitive assays. Vedolizumab and AVA were measured at week 6, at the last infusion, and 12–20 weeks after treatment discontinuation in a cohort of 40 vedolizumab‐treated IBD patients who stopped treatment due to primary non‐response, loss of response, or adverse events. Results The drug‐tolerant ACE assay could detect AVA in samples that the drug‐resistant and drug‐sensitive assays were unable to. Using the drug‐tolerant ACE assay, 3 (8%) out of 40 vedolizumab‐treated IBD patients who discontinued therapy were AVA positive at week 6, whereas no AVA were detected at the last infusion nor after treatment discontinuation. Primary non‐responders had numerically lower median vedolizumab concentrations at week 6 compared with patients with loss of response (20.3 vs 30.7 μg/mL, respectively, P = 0.0570). Conclusions Immunogenicity of vedolizumab is not the driving force of treatment failure, and AVA do not increase upon treatment discontinuation in vedolizumab‐treated IBD patients. Underexposure during induction might partially be responsible for primary non‐response.

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“…While TDM has been extensively studied and implemented when using tumour necrosis factor‐α (TNFα) antagonists, it's role in the optimisation of vedolizumab is unclear. Vedolizumab trough concentrations have been variably associated with clinical outcomes in patients with IBD, with some studies suggesting higher vedolizumab trough concentrations in patients responding to therapy, whereas others suggesting no differences in trough concentrations in responding vs nonresponding patients . In in vitro cell‐based assays, complete α 4 β 7 receptor saturation was reached at a vedolizumab serum concentration of approximately 1 μg/mL, a concentration considered subtherapeutic .…”

Section: Introductionmentioning

confidence: 99%

Systematic review with meta‐analysis: association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases

Singh

Dulai

Casteele

et al. 2019

Aliment Pharmacol Ther

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SUMMARY Background There has been limited evaluation of the association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases (IBD). Aim To perform a systematic review and meta‐analysis to evaluate the potential role of therapeutic drug monitoring (TDM) for vedolizumab. Methods Through a systematic literature search through 28 February 2019, we identified five cohort studies (558 patients, 42% with ulcerative colitis) reporting the association between vedolizumab trough concentration and clinical outcomes in patients with IBD. We calculated mean difference (MD) in vedolizumab trough concentration in patients achieving vs not achieving clinical outcomes, and qualitatively synthesized thresholds associated with favourable outcomes. Results In patients with UC, median vedolizumab trough concentrations were consistently higher in patients achieving clinical remission (median, 14.3 μg/mL vs 10.5 μg/mL; MD, 5.1 μg/mL, 95% CI, 2.8‐7.4) or endoscopic remission (median, 13.0 μg/mL vs 9.7; MD, 5.1 μg/mL, 95% CI, 2.2‐7.9). In patients with CD, there was no significant difference in median vedolizumab trough concentrations in patients achieving vs not achieving clinical remission (MD, 2.0 μg/mL; 95% CI, −0.5 to 4.5) or endoscopic remission (MD, 3.6 μg/mL; 95% CI, −1.4 to 8.6). In patients with UC, week 6 vedolizumab trough concentrations ≥18.5‐20.8 μg/mL, and maintenance trough concentrations ≥9.0‐12.6 μg/mL were associated with favourable clinical outcomes. Antibodies to vedolizumab were reported in 1.7%‐3.0% patients on maintenance therapy. Conclusion Based on meta‐analysis, patients with UC who achieve endoscopic and clinical remission have significantly higher vedolizumab trough concentration during maintenance therapy. Vedolizumab trough concentration >20 μg/mL at week 6, and >12 μg/mL during maintenance may be associated with better outcomes, though cause‐effect relationship remains unclear. Prospective studies on reactive and proactive therapeutic drug monitoring of vedolizumab (vs empiric dose escalation) are warranted.

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Association Between Low Trough Levels of Vedolizumab During Induction Therapy for Inflammatory Bowel Diseases and Need for Additional Doses Within 6 Months

Cited by 108 publications

References 10 publications

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation

Immunogenicity is not the driving force of treatment failure in vedolizumab‐treated inflammatory bowel disease patients

Systematic review with meta‐analysis: association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases

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