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Article

A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice

1
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany
2
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany
3
CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center of Infection and Immunity of Lille, University Lille, 59019 Lille, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Victor Mangas Sanjuán and Inaki F. Troconiz
Pharmaceutics 2021, 13(4), 469; https://doi.org/10.3390/pharmaceutics13040469
Received: 26 February 2021 / Revised: 24 March 2021 / Accepted: 25 March 2021 / Published: 30 March 2021
(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)
Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response relationship of amoxicillin with MPLA coadministration and establish a link to survival. Antibiotic serum concentrations, bacterial numbers in lung and spleen and survival data of mice being untreated or treated with amoxicillin (four dose levels), MPLA, or their combination were analyzed by nonlinear mixed-effects modelling and time-to-event analysis using NONMEM® to characterize these treatment regimens. On top of a pharmacokinetic interaction, regarding the pharmacodynamic effects the combined treatment was superior to both monotherapies: The amoxicillin efficacy at highest dose was increased by a bacterial reduction of 1.74 log10 CFU/lung after 36 h and survival was increased 1.35-fold to 90.3% after 14 days both compared to amoxicillin alone. The developed pharmacometric pharmacokinetic/pharmacodynamic disease-treatment-survival models provided quantitative insights into a novel treatment option against pneumonia revealing a pharmacokinetic interaction and enhanced activity of amoxicillin and the immune system stimulator MPLA in combination. Further development of this drug combination flanked with pharmacometrics towards the clinical setting seems promising. View Full-Text
Keywords: pharmacometric PK/PD modelling; time-to-event modelling; amoxicillin; MPLA; immunomodulation; murine model pharmacometric PK/PD modelling; time-to-event modelling; amoxicillin; MPLA; immunomodulation; murine model
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MDPI and ACS Style

Franck, S.; Michelet, R.; Casilag, F.; Sirard, J.-C.; Wicha, S.G.; Kloft, C. A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice. Pharmaceutics 2021, 13, 469. https://doi.org/10.3390/pharmaceutics13040469

AMA Style

Franck S, Michelet R, Casilag F, Sirard J-C, Wicha SG, Kloft C. A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice. Pharmaceutics. 2021; 13(4):469. https://doi.org/10.3390/pharmaceutics13040469

Chicago/Turabian Style

Franck, Sebastian; Michelet, Robin; Casilag, Fiordiligie; Sirard, Jean-Claude; Wicha, Sebastian G.; Kloft, Charlotte. 2021. "A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice" Pharmaceutics 13, no. 4: 469. https://doi.org/10.3390/pharmaceutics13040469

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