The Use of Translational Modelling and ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Title :
The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia
Author(s) :
Michelet, Robin [Auteur correspondant]
Freie Universität Berlin
Ursino, Moreno [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables [ECEVE (U1123 / UMR_S_1123)]
Boulet, Sandrine [Auteur]
Health data- and model- driven Knowledge Acquisition [HeKA]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Franck, Sebastian [Auteur]
Universität Hamburg = University of Hamburg [UHH]
Freie Universität Berlin
Casilag, Fiordiligie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Baldry, Mara [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Rolff, Jens [Auteur]
Freie Universität Berlin
van Dyk, Madelé [Auteur]
Flinders University [Adelaide, Australia]
Wicha, Sebastian [Auteur]
Universität Hamburg = University of Hamburg [UHH]
Sirard, Jean-Claude [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Comets, Emmanuelle [Auteur]
Infection, Anti-microbiens, Modélisation, Evolution [IAME (UMR_S_1137 / U1137)]
Centre d'Investigation Clinique [Rennes] [CIC]
Zohar, Sarah [Auteur]
Health data- and model- driven Knowledge Acquisition [HeKA]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Kloft, Charlotte [Auteur]
Freie Universität Berlin
Freie Universität Berlin
Ursino, Moreno [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables [ECEVE (U1123 / UMR_S_1123)]
Boulet, Sandrine [Auteur]

Health data- and model- driven Knowledge Acquisition [HeKA]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Franck, Sebastian [Auteur]
Universität Hamburg = University of Hamburg [UHH]
Freie Universität Berlin
Casilag, Fiordiligie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Baldry, Mara [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Rolff, Jens [Auteur]
Freie Universität Berlin
van Dyk, Madelé [Auteur]
Flinders University [Adelaide, Australia]
Wicha, Sebastian [Auteur]
Universität Hamburg = University of Hamburg [UHH]
Sirard, Jean-Claude [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Comets, Emmanuelle [Auteur]
Infection, Anti-microbiens, Modélisation, Evolution [IAME (UMR_S_1137 / U1137)]
Centre d'Investigation Clinique [Rennes] [CIC]
Zohar, Sarah [Auteur]
Health data- and model- driven Knowledge Acquisition [HeKA]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Kloft, Charlotte [Auteur]
Freie Universität Berlin
Journal title :
PHARMACEUTICS
Pages :
601
Publisher :
MDPI
Publication date :
2021-04-22
ISSN :
1999-4923
English keyword(s) :
Innate immunity
Extrapolation
Dose estimation
Antibacterial resistance
Anti-infective therapy
PK/PD
Bayesian inference
Pharmacometrics
Pneumonia
Translational modelling
Extrapolation
Dose estimation
Antibacterial resistance
Anti-infective therapy
PK/PD
Bayesian inference
Pharmacometrics
Pneumonia
Translational modelling
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept ...
Show more >The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the development of immunomodulatory therapeutic agents as an adjunct to antibiotics in the context of pneumonia. For this, two case studies of translational modelling and simulation frameworks are introduced for these types of drugs up to clinical use. First, we evaluate the pharmacokinetic/pharmacodynamic relationship of an experimental combination of amoxicillin and a TLR4 agonist, monophosphoryl lipid A, by developing a pharmacometric model accounting for interaction and potential translation to humans. Capitalizing on this knowledge and associating clinical trial extrapolation and statistical modelling approaches, we then investigate the TLR5 agonist flagellin. The resulting workflow combines expert and prior knowledge on the compound with the in vitro and in vivo data generated during exploratory studies in order to construct high-dimensional models considering the pharmacokinetics and pharmacodynamics of the compound. This workflow can be used to refine preclinical experiments, estimate the best doses for human studies, and create an adaptive knowledge-based design for the next phases of clinical development.Show less >
Show more >The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the development of immunomodulatory therapeutic agents as an adjunct to antibiotics in the context of pneumonia. For this, two case studies of translational modelling and simulation frameworks are introduced for these types of drugs up to clinical use. First, we evaluate the pharmacokinetic/pharmacodynamic relationship of an experimental combination of amoxicillin and a TLR4 agonist, monophosphoryl lipid A, by developing a pharmacometric model accounting for interaction and potential translation to humans. Capitalizing on this knowledge and associating clinical trial extrapolation and statistical modelling approaches, we then investigate the TLR5 agonist flagellin. The resulting workflow combines expert and prior knowledge on the compound with the in vitro and in vivo data generated during exploratory studies in order to construct high-dimensional models considering the pharmacokinetics and pharmacodynamics of the compound. This workflow can be used to refine preclinical experiments, estimate the best doses for human studies, and create an adaptive knowledge-based design for the next phases of clinical development.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Source :
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