Wicha, SG; Clewe, O; Svensson, RJ; Gillespie, SH; Hu, Y; Coates, ARM; Simonsson, USH
(2018)
Forecasting Clinical Dose–Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin.
Clin Pharmacol Ther, 104 (6).
pp. 1208-1218.
ISSN 1532-6535
https://doi.org/10.1002/cpt.1102
SGUL Authors: Coates, Anthony Robert Milnes Hu, Yanmin
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Abstract
A crucial step for accelerating tuberculosis drug development is bridging the gap between preclinical and clinical trials. In this study, we developed a preclinical model‐informed translational approach to predict drug effects across preclinical systems and early clinical trials using the in vitro‐based Multistate Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP model predicted rifampicin biomarker response observed in 1) a hollow‐fiber infection model, 2) a murine study to determine pharmacokinetic/pharmacodynamic indices, and 3) several clinical phase IIa early bactericidal activity (EBA) studies. In addition, we predicted rifampicin biomarker response at high doses of up to 50 mg/kg, leading to an increased median EBA0‐2 days (90% prediction interval) of 0.513 log CFU/mL/day (0.310; 0.701) compared to the standard dose of 10 mg/kg of 0.181 log/CFU/mL/day (0.076; 0.483). These results suggest that the translational approach could assist in the selection of drugs and doses in early‐phase clinical tuberculosis trials.
Item Type: | Article | |||||||||
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Additional Information: | © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. | |||||||||
Keywords: | forward translational, rifampicin, tuberculosis, Pharmacology & Pharmacy, 1115 Pharmacology And Pharmaceutical Sciences | |||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Infection and Immunity Research Institute (INII) | |||||||||
Journal or Publication Title: | Clin Pharmacol Ther | |||||||||
ISSN: | 1532-6535 | |||||||||
Language: | eng | |||||||||
Publisher License: | Creative Commons: Attribution-Noncommercial 4.0 | |||||||||
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PubMed ID: | 29700814 | |||||||||
Go to PubMed abstract | ||||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/109775 | |||||||||
Publisher's version: | https://doi.org/10.1002/cpt.1102 |
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