Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment...

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Autores principales:	David Ternant, Olivier Le Tilly, Laurence Picon, Driffa Moussata, Christophe Passot, Theodora Bejan-Angoulvant, Céline Desvignes, Denis Mulleman, Philippe Goupille, Gilles Paintaud
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	infliximab pharmacokinetics target-mediated drug disposition inflammatory bowel diseases Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/e2d78037197449f6a4091c5a92ae7319
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spelling	oai:doaj.org-article:e2d78037197449f6a4091c5a92ae73192021-11-25T18:40:55ZInfliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model10.3390/pharmaceutics131118211999-4923https://doaj.org/article/e2d78037197449f6a4091c5a92ae73192021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1821https://doaj.org/toc/1999-4923Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (R<sup>C</sup><sub>0</sub> = 3.3 nM and R<sup>P</sup><sub>0</sub> = 0.46 nM), steady-stated dissociation rates (K<sup>C</sup><sub>SS</sub> = 15.4 nM and K<sup>P</sup><sub>SS</sub> = 0.49 nM), and first-order elimination rates of complexes (k<sup>C</sup><sub>int</sub> = 0.17 day<sup>−1</sup> and k<sup>P</sup><sub>int</sub> = 0.0079 day<sup>−1</sup>). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.David TernantOlivier Le TillyLaurence PiconDriffa MoussataChristophe PassotTheodora Bejan-AngoulvantCéline DesvignesDenis MullemanPhilippe GoupilleGilles PaintaudMDPI AGarticleinfliximabpharmacokineticstarget-mediated drug dispositioninflammatory bowel diseasesPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1821, p 1821 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	infliximab pharmacokinetics target-mediated drug disposition inflammatory bowel diseases Pharmacy and materia medica RS1-441
spellingShingle	infliximab pharmacokinetics target-mediated drug disposition inflammatory bowel diseases Pharmacy and materia medica RS1-441 David Ternant Olivier Le Tilly Laurence Picon Driffa Moussata Christophe Passot Theodora Bejan-Angoulvant Céline Desvignes Denis Mulleman Philippe Goupille Gilles Paintaud Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model
description	Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (R<sup>C</sup><sub>0</sub> = 3.3 nM and R<sup>P</sup><sub>0</sub> = 0.46 nM), steady-stated dissociation rates (K<sup>C</sup><sub>SS</sub> = 15.4 nM and K<sup>P</sup><sub>SS</sub> = 0.49 nM), and first-order elimination rates of complexes (k<sup>C</sup><sub>int</sub> = 0.17 day<sup>−1</sup> and k<sup>P</sup><sub>int</sub> = 0.0079 day<sup>−1</sup>). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.
format	article
author	David Ternant Olivier Le Tilly Laurence Picon Driffa Moussata Christophe Passot Theodora Bejan-Angoulvant Céline Desvignes Denis Mulleman Philippe Goupille Gilles Paintaud
author_facet	David Ternant Olivier Le Tilly Laurence Picon Driffa Moussata Christophe Passot Theodora Bejan-Angoulvant Céline Desvignes Denis Mulleman Philippe Goupille Gilles Paintaud
author_sort	David Ternant
title	Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model
title_short	Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model
title_full	Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model
title_fullStr	Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model
title_full_unstemmed	Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model
title_sort	infliximab efficacy may be linked to full tnf-α blockade in peripheral compartment—a double central-peripheral target-mediated drug disposition (tmdd) model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e2d78037197449f6a4091c5a92ae7319
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Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

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