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Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection.


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.

SUBMITTER: Kloprogge F 

PROVIDER: S-EPMC6744479 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection.

Kloprogge Frank F   Hammond Robert R   Kipper Karin K   Gillespie Stephen H SH   Della Pasqua Oscar O  

Scientific reports 20190913 1


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 C<sub>MAX</sub>, T  ...[more]

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