TY - JOUR
T1 - Mimicking in-vivo exposures to drug combinations in-vitro
T2 - anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection
AU - Kloprogge, Frank
AU - Hammond, Robert
AU - Kipper, Karin
AU - Gillespie, Stephen H.
AU - Della Pasqua, Oscar
N1 - 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).
PY - 2019/9/13
Y1 - 2019/9/13
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-019-49556-5
DO - 10.1038/s41598-019-49556-5
M3 - Article
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
M1 - 13228
ER -
