Files in this item
Mimicking in-vivo exposures to drug combinations in-vitro : anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
Item metadata
dc.contributor.author | Kloprogge, Frank | |
dc.contributor.author | Hammond, Robert | |
dc.contributor.author | Kipper, Karin | |
dc.contributor.author | Gillespie, Stephen H. | |
dc.contributor.author | Della Pasqua, Oscar | |
dc.date.accessioned | 2019-09-17T15:30:04Z | |
dc.date.available | 2019-09-17T15:30:04Z | |
dc.date.issued | 2019-09-13 | |
dc.identifier | 261216185 | |
dc.identifier | 5dcaff00-d399-46b9-a79b-43ae9adc83de | |
dc.identifier | 85072171904 | |
dc.identifier | 000485680900025 | |
dc.identifier.citation | Kloprogge , F , Hammond , R , Kipper , K , Gillespie , S H & Della Pasqua , O 2019 , ' Mimicking in-vivo exposures to drug combinations in-vitro : anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection ' , Scientific Reports , vol. 9 , 13228 . https://doi.org/10.1038/s41598-019-49556-5 | en |
dc.identifier.issn | 2045-2322 | |
dc.identifier.other | RIS: urn:8AD5BF285DF1CCE91CF46252115AEB26 | |
dc.identifier.other | RIS: Kloprogge2019 | |
dc.identifier.other | ORCID: /0000-0001-6537-7712/work/61978861 | |
dc.identifier.other | ORCID: /0000-0003-3664-3641/work/157140939 | |
dc.identifier.uri | https://hdl.handle.net/10023/18495 | |
dc.description | This research was supported by a British Society of Antimicrobial Chemotherapy Grant (GA2015-172R). FK has conducted the research as part of a Medical Research Council fellowship (MR/P014534/1) and consumables to develop the ultra-high-performance liquid chromatographic-tandem mass spectrometric detection method and analyse the samples were paid to Analytical Services International Ltd. from a Medical Research Council fellowship (MR/P014534/1). | en |
dc.description.abstract | Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung lesion homogenate were simulated for isoniazid, rifampicin and pyrazinamide and moxifloxacin. An R-shiny User Interface was developed to support conversion of in-vivo pharmacokinetic CMAX, TMAX and T1/2 estimates into pump settings. A monotherapy protocol mimicking isoniazid in lung lesion homogenate (isoniazid CMAX = 1,200 ng/ml, TMAX = 2.2 hr and T1/2 = 4.7 hr), and two combination therapy protocols including drugs with similar (isoniazid and rifampicin (CMAX = 400 ng/ml)) and different half-lives (isoniazid and pyrazinamide (CMAX = 28,900 ng/ml and T1/2 = 8.0 hr)) were implemented in a hollow-fiber system. Drug levels in the perfusate were analysed using ultra-high-performance liquid chromatographic-tandem mass spectrometric detection. Steady state pharmacokinetic profiles measured in the hollow fiber model were similar to the predicted in-vivo steady-state lung lesion homogenate pharmacokinetic profiles. The presented approach offers the possibility to use pharmacological data to study the effect of target tissue exposure for drug combinations. Integration with pharmacokinetics modelling principles through a web interface will provide access to a wider community interested in the evaluation of efficacy of anti-tubercular drugs. | |
dc.format.extent | 8 | |
dc.format.extent | 2076926 | |
dc.language.iso | eng | |
dc.relation.ispartof | Scientific Reports | en |
dc.subject | RM Therapeutics. Pharmacology | en |
dc.subject | NDAS | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | RM | en |
dc.title | Mimicking in-vivo exposures to drug combinations in-vitro : anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. School of Medicine | en |
dc.contributor.institution | University of St Andrews. Infection and Global Health Division | en |
dc.contributor.institution | University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis | en |
dc.contributor.institution | University of St Andrews. Centre for Biophotonics | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. Global Health Implementation Group | en |
dc.contributor.institution | University of St Andrews. Gillespie Group | en |
dc.contributor.institution | University of St Andrews. Infection Group | en |
dc.identifier.doi | 10.1038/s41598-019-49556-5 | |
dc.description.status | Peer reviewed | en |
This item appears in the following Collection(s)
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.