SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Translational Model-Informed Approach for Selection of Tuberculosis Drug Combination Regimens in Early Clinical Development.

Susanto, BO; Wicha, SG; Hu, Y; Coates, ARM; Simonsson, USH (2020) Translational Model-Informed Approach for Selection of Tuberculosis Drug Combination Regimens in Early Clinical Development. Clin Pharmacol Ther. ISSN 1532-6535 https://doi.org/10.1002/cpt.1814
SGUL Authors: Coates, Anthony Robert Milnes Hu, Yanmin

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution Non-commercial.

Download (627kB) | Preview
[img]
Preview
PDF Accepted Version
Available under License Creative Commons Attribution Non-commercial.

Download (1MB) | Preview

Abstract

The development of optimal treatment regimens in tuberculosis (TB) remains challenging due to the need of combination therapy and possibility of pharmacodynamic (PD) interactions. Preclinical information about PD interactions needs to be used more optimally when designing early bactericidal activity (EBA) studies. In this work, we developed a translational approach which can allow for forward translation to predict efficacy of drug combination in EBA studies using the Multistate Tuberculosis Pharmacometric (MTP) and the General Pharmacodynamic Interaction (GPDI) models informed by in vitro static time-kill data. These models were linked with translational factors to account for differences between the in vitro system and humans. Our translational MTP-GPDI model approach was able to predict the EBA0-2 days , EBA0-5 days , and EBA0-14 days from different EBA studies of rifampicin and isoniazid in monotherapy and combination. Our translational model approach can contribute to an optimal dose selection of drug combinations in early TB clinical trials.

Item Type: Article
Additional Information: © 2020 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 (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: model-based drug development, pharmacodynamic interactions, tuberculosis, 1115 Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
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
Dates:
DateEvent
2 April 2020Published Online
8 February 2020Accepted
Publisher License: Creative Commons: Attribution-Noncommercial 4.0
Projects:
Project IDFunderFunder ID
521‐2011‐3442Swedish Research Council Formashttp://dx.doi.org/10.13039/501100001862
115337Innovative Medicines Initiative Joint UndertakingUNSPECIFIED
PubMed ID: 32080839
Web of Science ID: WOS:000523244700001
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111706
Publisher's version: https://doi.org/10.1002/cpt.1814

Actions (login required)

Edit Item Edit Item