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Evaluation of pharmacokinetic‐pharmacodynamic relationships and selection of drug combinations for tuberculosis

Muliaditan, M; Della Pasqua, O; (2020) Evaluation of pharmacokinetic‐pharmacodynamic relationships and selection of drug combinations for tuberculosis. British Journal of Clinical Pharmacology 10.1111/bcp.14371. (In press). Green open access

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Abstract

AIMS: Despite evidence of the efficacy of anti-tubercular drug regimens in clinical practice, the rationale underpinning the selection of doses and companion drugs for combination therapy remains empirical. Novel methods are needed to optimise the antibacterial activity in combination therapies. A drug-disease modelling framework for rational selection of dose and drug combinations in tuberculosis is presented here. METHODS: A model-based meta-analysis was performed to assess the antibacterial activity of different combinations in infected mice. Data retrieved from the published literature were analysed using a two-state bacterial growth dynamics model, including fast- and slow-growing bacterial populations. The contribution of each drug to the overall antibacterial activity of the combination was parameterised as relative change to the potency of the backbone drug (EC50 -F and/or EC50 -S). Rifampicin and bedaquiline were selected as paradigm drugs to evaluate the predictive performance of the modelling approach. RESULTS: Pyrazinamide increased the EC50 -F and EC50 -S of rifampicin (RZ) and bedaquiline (BZ) by almost two-fold. By contrast, pretomanid and isoniazid were found to worsen the antibacterial activity of BZ and RZ, respectively. Following extrapolation of in vivo pharmacokinetic-pharmacodynamic relationships, the dose of rifampicin showing maximum bactericidal effect in tuberculosis patients was predicted to be 70 mg·kg-1 when given in combination with pyrazinamide. CONCLUSIONS: The use of a drug-disease modelling framework may provide a more robust rationale for extrapolation and selection of dose and companion drugs in humans. Our analysis demonstrates that RZ and BZ should be considered as a backbone therapy in prospective novel combination regimens against tuberculosis.

Type: Article
Title: Evaluation of pharmacokinetic‐pharmacodynamic relationships and selection of drug combinations for tuberculosis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bcp.14371
Publisher version: https://doi.org/10.1111/bcp.14371
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: bedaquiline, combination therapy, dose rationale, rifampicin, translational pharmacokinetic-pharmacodynamic modelling, 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.ucl.ac.uk/id/eprint/10099106
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