P-140 Pharmacokinetic/Pharmacodynamic Relationship and Immunogenicity of Vedolizumab in Adults with Inflammatory Bowel Disease
Notice bibliographique
Résumé
Vedolizumab is a humanized immunoglobulin G1 monoclonal antibody that exclusively targets the lymphocyte integrin α4β7. This interaction prevents the binding of gut-homing T lymphocytes to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), thus reducing gastrointestinal inflammation. Vedolizumab is currently in development for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). Vedolizumab pharmacokinetic (PK) data from phase 3 studies (GEMINI 1 and 2) have been previously published and show similar PK profiles in UC and CD patient populations.1,2 Here the PK/pharmacodynamic (PD) relationship and immunogenicity of vedolizumab in the GEMINI 1 and 2 studies are described. The GEMINI 1 and 2 studies included a 6-week induction phase, during which patients received vedolizumab 300 mg or placebo intravenously at weeks 0 and 2 and were assessed at week 6. Vedolizumab-treated patients who had a clinical response at week 6 were randomly assigned to receive vedolizumab 300 mg (vedolizumab intention-to-treat [ITT] population) or placebo (placebo ITT population) every 4 weeks (Q4W) or every 8 weeks (Q8W) during the subsequent 46-week maintenance phase. Vedolizumab induction nonresponders (non-ITT population) received open-label vedolizumab Q4W, and patients randomly assigned to placebo during the induction phase continued to receive placebo until week 52. Blood samples for determination of vedolizumab concentrations, PD assessment (α4β7 [receptor] saturation via MAdCAM-1-Fc binding interference assay), and anti-vedolizumab antibody assessment were collected at prespecified time points. Descriptive statistics were used to summarize vedolizumab PK and immunogenicity data. Plots of receptor saturation were generated. Administration of vedolizumab 300 mg Q4W or Q8W resulted in mean serum concentrations ≥10 µg/mL at all time points in both UC and CD patients (ITT and non-ITT). In a pooled analysis of UC and CD patients (ITT and non-ITT), complete receptor saturation was observed at week 6 and maintained until week 52 in both the vedolizumab Q8W and Q4W groups. Overall, 4% (56/1434) of patients tested positive for anti-vedolizumab antibodies at any time during vedolizumab treatment. Frequency of anti-vedolizumab antibody development off drug (week 66) was ∼10% (32/320) in pooled UC and CD patients (ITT and non-ITT). Among patients who had an investigator-defined infusion-related reaction, 5% (3/61) tested persistently (at ≥2 consecutive visits) positive for anti-vedolizumab antibodies. Compared with the general study population, patients who tested persistently positive for anti-vedolizumab antibodies generally had lower serum vedolizumab trough concentrations. In the ITT placebo group, use of concomitant immunomodulators was associated with a lower rate of anti-vedolizumab antibody positivity (3%, 1/32) than seen without use of concomitant immunomodulators (18%, 44/247). Conclusions During dosing with vedolizumab either Q8W or Q4W in patients with UC and CD, mean vedolizumab serum concentrations were maintained at ≥10 µg/mL, a level that resulted in complete receptor saturation. References 1. Sandborn WJ, et al. N Engl J Med. 2013;369(8):711-721. 2. Feagan BG, et al. N Engl J Med. 2013;369(8):699-710.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».