Muliaditan, M;
Della Pasqua, O;
(2021)
Bacterial growth dynamics and PKPD relationships of rifampicin and bedaquiline in BALB/c mice.
British Journal of Pharmacology
, 179
(6)
pp. 1251-1263.
10.1111/bph.15688.
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Abstract
Background and Purpose: Translational efforts in the evaluation of novel anti-tubercular drugs demand better integration of pharmacokinetic–pharmacodynamic data arising from preclinical protocols. However, parametric approaches that discriminate drug effect from the underlying bacterial growth dynamics have not been fully explored, making it difficult to translate and/or extrapolate preclinical findings to humans. This analysis aims to develop a drug-disease model that allows distinction between drug- and system-specific properties. Experimental Approach: Given their clinical relevance, rifampicin and bedaquiline were used as test compounds. A two-state model was used to describe bacterial growth dynamics. The approach assumes the existence of fast- and slow-growing bacterial populations. Drug effect on the growth dynamics of each subpopulation was characterised in terms of potency (EC50-F and EC50-S) and maximum killing rate. Key Results: The doubling time of the fast- and slow-growing population was estimated to be 25 h and 42 days, respectively. Rifampicin was more potent against the fast-growing (EC50-F = 4.8 mg·L−1), as compared with the slow-growing population (EC50-S = 60.2 mg·L−1). Bedaquiline showed higher potency than rifampicin (EC50-F = 0.19 mg·L−1; EC50-S = 3.04 mg·L−1). External validation procedures revealed an effect of infection route on the apparent potency of rifampicin. Conclusion and Implications: Model parameter estimates suggest that nearly maximum killing rate is achieved against fast-growing, but not against slow-growing populations at the tested doses. Evidence of differences in drug potency for each subpopulation may facilitate the translation of preclinical findings and improve the dose rationale for anti-tubercular drugs in humans.
| Type: | Article |
|---|---|
| Title: | Bacterial growth dynamics and PKPD relationships of rifampicin and bedaquiline in BALB/c mice |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bph.15688 |
| Publisher version: | https://doi.org/10.1111/bph.15688 |
| Language: | English |
| Additional information: | © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | bedaquiline, human dose selection, PKPD modelling, rifampicin, translational pharmacology, tuberculosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10133849 |
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