Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study

BACKGROUND: Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedoli...

Descripción completa

Detalles Bibliográficos
Autores principales: Hanzel, Jurij, Dreesen, Erwin, Vermeire, Séverine, Löwenberg, Mark, Hoentjen, Frank, Bossuyt, Peter, Clasquin, Esmé, Baert, Filip J, D’Haens, Geert R, Mathôt, Ron
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9071095/
https://www.ncbi.nlm.nih.gov/pubmed/34137430
http://dx.doi.org/10.1093/ibd/izab143
_version_ 1784700776260567040
author Hanzel, Jurij
Dreesen, Erwin
Vermeire, Séverine
Löwenberg, Mark
Hoentjen, Frank
Bossuyt, Peter
Clasquin, Esmé
Baert, Filip J
D’Haens, Geert R
Mathôt, Ron
author_facet Hanzel, Jurij
Dreesen, Erwin
Vermeire, Séverine
Löwenberg, Mark
Hoentjen, Frank
Bossuyt, Peter
Clasquin, Esmé
Baert, Filip J
D’Haens, Geert R
Mathôt, Ron
author_sort Hanzel, Jurij
collection PubMed
description BACKGROUND: Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD. METHODS: Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD; ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4). RESULTS: Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naïve or previously exposed to biologic therapy, respectively. CONCLUSIONS: Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates.
format Online
Article
Text
id pubmed-9071095
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-90710952022-05-06 Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study Hanzel, Jurij Dreesen, Erwin Vermeire, Séverine Löwenberg, Mark Hoentjen, Frank Bossuyt, Peter Clasquin, Esmé Baert, Filip J D’Haens, Geert R Mathôt, Ron Inflamm Bowel Dis Clinical Research BACKGROUND: Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD. METHODS: Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD; ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4). RESULTS: Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naïve or previously exposed to biologic therapy, respectively. CONCLUSIONS: Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates. Oxford University Press 2021-06-17 /pmc/articles/PMC9071095/ /pubmed/34137430 http://dx.doi.org/10.1093/ibd/izab143 Text en © 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Clinical Research
Hanzel, Jurij
Dreesen, Erwin
Vermeire, Séverine
Löwenberg, Mark
Hoentjen, Frank
Bossuyt, Peter
Clasquin, Esmé
Baert, Filip J
D’Haens, Geert R
Mathôt, Ron
Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study
title Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study
title_full Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study
title_fullStr Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study
title_full_unstemmed Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study
title_short Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study
title_sort pharmacokinetic-pharmacodynamic model of vedolizumab for targeting endoscopic remission in patients with crohn disease: posthoc analysis of the love-cd study
topic Clinical Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9071095/
https://www.ncbi.nlm.nih.gov/pubmed/34137430
http://dx.doi.org/10.1093/ibd/izab143
work_keys_str_mv AT hanzeljurij pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT dreesenerwin pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT vermeireseverine pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT lowenbergmark pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT hoentjenfrank pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT bossuytpeter pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT clasquinesme pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT baertfilipj pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT dhaensgeertr pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy
AT mathotron pharmacokineticpharmacodynamicmodelofvedolizumabfortargetingendoscopicremissioninpatientswithcrohndiseaseposthocanalysisofthelovecdstudy