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Translational in vi...
Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia
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- Aranzana-Climent, Vincent (författare)
- Uppsala universitet,Institutionen för farmaci
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- Hughes, Diarmaid, 1956- (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Cao, Sha (författare)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Tomczak, Magdalena (författare)
- National Medicines Institute, Poland,Natl Med Inst, Dept Epidemiol & Clin Microbiol, Warsaw, Poland.
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- Urbas, Malgorzata (författare)
- National Medicines Institute, Poland,Natl Med Inst, Dept Epidemiol & Clin Microbiol, Warsaw, Poland.
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- Zabicka, Dorota (författare)
- Uppsala University, Sweden,Natl Med Inst, Dept Epidemiol & Clin Microbiol, Warsaw, Poland.
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- Vingsbo Lundberg, Carina (författare)
- Statens Serum Institut, Denmark,Statens Serum Inst, Bacteria Parasites & Fungi, Copenhagen, Denmark.
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- Hansen, Jon (författare)
- Statens Serum Institut, Denmark,Statens Serum Inst, Bacteria Parasites & Fungi, Copenhagen, Denmark.
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- Lindberg, Johan (författare)
- RISE,Kemisk och farmaceutisk toxikologi,RISE Res Inst Sweden, Södertälje, Sweden.
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- Hobbie, Sven N (författare)
- University of Zurich, Switzerland,Univ Zurich, Inst Med Microbiol, Zurich, Switzerland.
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- Friberg, Lena (författare)
- Uppsala universitet,Institutionen för farmaci
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(creator_code:org_t)
- Elsevier B.V. 2022
- 2022
- Engelska.
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Ingår i: Clinical Microbiology and Infection. - : Elsevier B.V.. - 1198-743X .- 1469-0691. ; 28:10, s. 1367-1374
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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)
Ämnesord
- TEKNIK OCH TEKNOLOGIER -- Industriell bioteknik -- Läkemedelsbioteknik (hsv//swe)
- ENGINEERING AND TECHNOLOGY -- Industrial Biotechnology -- Pharmaceutical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Nyckelord
- Apramycin
- Modelling
- Pharmacodynamics
- Pharmacokinetics
- Pharmacometrics
- Preclinical
- Translational
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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