Muliaditan, M;
Teutonico, D;
Ortega-Mur, F;
Ferre, S;
Della Pasqua, Oscar;
(2022)
Prediction of lung exposure to anti-tubercular drugs using plasma pharmacokinetic data: implications for dose selection.
European Journal of Pharmaceutical Sciences
, 173
, Article 106163. 10.1016/j.ejps.2022.106163.
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Abstract
The development of novel candidate molecules for tuberculosis remains challenging, as drug distribution into the target tissue is not fully characterised in preclinical models of infection. Often antitubercular human dose selection is derived from pharmacokinetic data in plasma. Here, we explore whether whole-body physiologically-based pharmacokinetic (PBPK) modelling enables the prediction of lung exposure to anti-tubercular drugs in humans. Whole-body PBPK models were developed for rifampicin, isoniazid, pyrazinamide, and ethambutol using plasma data in mice as basis for the prediction of lung exposure. Model parameters were subsequently used to extrapolate disposition properties from mouse and determine lung:plasma ratio in humans. Model predictions were compared to biopsy data from patients. Predictions were deemed adequate if they fell within two-fold range of the observations. The concentration vs time profiles in lung were adequately predicted in mice. Isoniazid and pyrazinamide lung exposures were predicted to be comparable to plasma levels, whereas ethambutol lung exposure was predicted to be higher than in plasma. Lung:plasma ratio in humans could be reasonably predicted from preclinical data, but was highly dependent on the distribution model. This analysis showed that plasma pharmacokinetics may be used in conjunction with PBPK modelling to derive lung tissue exposure in mice and humans during early lead optimisation phase. However, the impact of uncertainty in predicted tissue exposure due to distribution should be always investigated through a sensitivity analysis when only plasma data is available. Despite these limitations, insight into lung tissue distribution represents a critical step for the dose rationale in tuberculosis patients.
| Type: | Article |
|---|---|
| Title: | Prediction of lung exposure to anti-tubercular drugs using plasma pharmacokinetic data: implications for dose selection |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ejps.2022.106163 |
| Publisher version: | https://doi.org/10.1016/j.ejps.2022.106163 |
| Language: | English |
| Additional information: | © 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | PBPK modelling, Tuberculosis, Pharmacokinetics, Lung distribution, Rifampicin, Isoniazid, Ethambutol, Pyrazinamide |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144677 |
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