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Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia
Uppsala University, Sweden.
Uppsala University, Sweden.
Uppsala University, Sweden.
National Medicines Institute, Poland.
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2022 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 10, p. 1367-1374Article in journal (Refereed) Published
Abstract [en]

Objectives: New drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy. Methods: Three pneumonia-inducing gram-negative species Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied. Bactericidal kinetics were evaluated with time-kill curves; in vivo PK were studied in healthy and infected mice, with sampling in plasma and epithelial lining fluid after subcutaneous administration; in vivo efficacy was measured in a neutropenic mouse pneumonia model. A pharmacokinetic-pharmacodynamic model, integrating all the data, was developed and simulations were performed. Results: Good lung penetration of apramycin in epithelial lining fluid (ELF) was shown (area under the curve (AUC)ELF/AUCplasma = 88%). Plasma clearance was 48% lower in lung infected mice compared to healthy mice. For two out of five strains studied, a delay in growth (∼5 h) was observed in vivo but not in vitro. The mathematical model enabled integration of lung PK to drive mouse PK and pharmacodynamics. Simulations predicted that 30 mg/kg of apramycin once daily would result in bacteriostasis in patients. Discussion: Apramycin is a candidate for treatment of carbapenem-resistant gram-negative pneumonia as demonstrated in an integrated modeling framework for three bacterial species. We show that mathematical modelling is a useful tool for simultaneous inclusion of multiple data sources, notably plasma and lung in vivo PK and simulation of expected scenarios in a clinical setting, notably lung infections. © 2022 The Author(s)

Place, publisher, year, edition, pages
Elsevier B.V. , 2022. Vol. 28, no 10, p. 1367-1374
Keywords [en]
Apramycin, Modelling, Pharmacodynamics, Pharmacokinetics, Pharmacometrics, Preclinical, Translational
National Category
Pharmaceutical Biotechnology
Identifiers
URN: urn:nbn:se:ri:diva-59864DOI: 10.1016/j.cmi.2022.05.003Scopus ID: 2-s2.0-85133746272OAI: oai:DiVA.org:ri-59864DiVA, id: diva2:1685109
Note

 Funding details: National Institutes of Health, NIH, HHSN272201700020I 75N93019F00131; Funding details: National Institute of Allergy and Infectious Diseases, NIAID; Funding details: Seventh Framework Programme, FP7; Funding details: European Federation of Pharmaceutical Industries and Associations, EFPIA, W187/IMI/2014; Funding details: Vetenskapsrådet, VR, 2018-03296; Funding details: Ministerstwo Edukacji i Nauki, MNiSW; Funding details: Universität Zürich, UZH; Funding details: Innovative Medicines Initiative, IMI, 115583; Funding text 1: Some of the research leading to these results was conducted as part of the ND4BB European Gram-Negative Antibacterial Engine (ENABLE) Consortium ( www.nd4bb-enable.eu ) and has received funding from the Innovative Medicines Initiative Joint Undertaking ( www.imi.europa.eu ) under grant agreement no. 115583, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and The European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution. The ENABLE project is also financially supported by contributions from academic and small and medium-sized enterprise (SME) partners. This work was in part financially supported by the ENABLE supplementary grant W187/IMI/2014 from the Polish Ministry of Science and Higher Education. The University of Zurich has utilized the suite of preclinical services for in-vivo assessment offered by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) (Contract Nos. HHSN272201700020I 75N93020F00159 and HHSN272201700020I 75N93019F00131, with Pharmacology Discovery Services Taiwan, a Eurofins Discovery Partner Lab). VAC was also supported by the Swedish Research Council [grant no. 2018-03296 to LF]. SNH is a Co-Founder of Juvabis AG, which develops apramycin for human use. The other authors have no conflict of interest to declare in addition to the funding for the study detailed above. These results have been partially presented at the 31st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).; Funding text 2: Some of the research leading to these results was conducted as part of the ND4BB European Gram-Negative Antibacterial Engine (ENABLE) Consortium (www.nd4bb-enable.eu) and has received funding from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement no. 115583, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and The European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution. The ENABLE project is also financially supported by contributions from academic and small and medium-sized enterprise (SME) partners. This work was in part financially supported by the ENABLE supplementary grant W187/IMI/2014 from the Polish Ministry of Science and Higher Education. The University of Zurich has utilized the suite of preclinical services for in-vivo assessment offered by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) (Contract Nos. HHSN272201700020I 75N93020F00159 and HHSN272201700020I 75N93019F00131, with Pharmacology Discovery Services Taiwan, a Eurofins Discovery Partner Lab). VAC was also supported by the Swedish Research Council [grant no. 2018-03296 to LF]. SNH is a Co-Founder of Juvabis AG, which develops apramycin for human use. The other authors have no conflict of interest to declare in addition to the funding for the study detailed above. These results have been partially presented at the 31st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Available from: 2022-08-01 Created: 2022-08-01 Last updated: 2023-07-06Bibliographically approved

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