Next Article in Journal
Effective Photodynamic Therapy with Ir(III) for Virulent Clinical Isolates of Extended-Spectrum Beta-Lactamase Klebsiella pneumoniae
Next Article in Special Issue
The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials
Previous Article in Journal
Enhanced Anticancer Efficacy of Dual Drug-Loaded Self-Assembled Nanostructured Lipid Carriers Mediated by pH-Responsive Folic Acid and Human-Derived Cell Penetrating Peptide dNP2
Previous Article in Special Issue
Matrix Effects of the Hydroethanolic Extract of Calyces of Physalis peruviana L. on Rutin Pharmacokinetics in Wistar Rats Using Population Modeling
Article

The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia

1
Department of Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany
2
Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, CHU Robert Debré, Université de Paris, Sorbonne Paris-Cité, Inserm U1123 and CIC-EC 1426, F-75019 Paris, France
3
INSERM, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, F-75006 Paris, France
4
HeKA, Inria, F-75006 Paris, France
5
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany
6
CNRS, Inserm, CHU Lille, Institute Pasteur de Lille, U1019-UMR9017-CIIL-Centre for Infection and Immunity of Lille, Université de Lille, F-59000 Lille, France
7
Department of Evolutionary Biology, Institute of Biology, Freie Universitaet Berlin, 14195 Berlin, Germany
8
Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
9
INSERM, University Rennes-1, CIC 1414, F-35000 Rennes, France
10
INSERM, IAME, Université de Paris, F-75006 Paris, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Victor Mangas Sanjuán
Pharmaceutics 2021, 13(5), 601; https://doi.org/10.3390/pharmaceutics13050601
Received: 28 February 2021 / Revised: 16 April 2021 / Accepted: 20 April 2021 / Published: 22 April 2021
(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)
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. View Full-Text
Keywords: pharmacometrics; translational modelling; anti-infective therapy; antibacterial resistance; innate immunity; pneumonia; dose estimation; PK/PD; Bayesian inference; extrapolation pharmacometrics; translational modelling; anti-infective therapy; antibacterial resistance; innate immunity; pneumonia; dose estimation; PK/PD; Bayesian inference; extrapolation
Show Figures

Figure 1

MDPI and ACS Style

Michelet, R.; Ursino, M.; Boulet, S.; Franck, S.; Casilag, F.; Baldry, M.; Rolff, J.; van Dyk, M.; Wicha, S.G.; Sirard, J.-C.; Comets, E.; Zohar, S.; Kloft, C. The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia. Pharmaceutics 2021, 13, 601. https://doi.org/10.3390/pharmaceutics13050601

AMA Style

Michelet R, Ursino M, Boulet S, Franck S, Casilag F, Baldry M, Rolff J, van Dyk M, Wicha SG, Sirard J-C, Comets E, Zohar S, Kloft C. The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia. Pharmaceutics. 2021; 13(5):601. https://doi.org/10.3390/pharmaceutics13050601

Chicago/Turabian Style

Michelet, Robin, Moreno Ursino, Sandrine Boulet, Sebastian Franck, Fiordiligie Casilag, Mara Baldry, Jens Rolff, Madelé van Dyk, Sebastian G. Wicha, Jean-Claude Sirard, Emmanuelle Comets, Sarah Zohar, and Charlotte Kloft. 2021. "The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia" Pharmaceutics 13, no. 5: 601. https://doi.org/10.3390/pharmaceutics13050601

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop