P-140 Pharmacokinetic/Pharmacodynamic Relationship and Immunogenicity of Vedolizumab in Adults with Inflammatory Bowel Disease
Bibliographic record
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".