The use of translational modelling and simulation to develop immunomodulatory therapy as an adjunct to antibiotic treatment in the context of pneumonia

Robin Michelet, 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, Charlotte Kloft

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.

    Original languageEnglish
    Article number601
    Number of pages12
    JournalPharmaceutics
    Volume13
    Issue number5
    DOIs
    Publication statusPublished - May 2021

    Keywords

    • Anti-infective therapy
    • Antibacterial resistance
    • Bayesian inference
    • Dose estimation
    • Extrapolation
    • Innate immunity
    • Pharmacometrics
    • PK/PD
    • Pneumonia
    • Translational modelling

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