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Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration

Aljayyoussi, Ghaith, Jenkins, Victoria, Sharma, Raman, Donnellan, Samantha, Ward, Steve and Biagini, Giancarlo (2017) 'Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration'. Scientific Reports, Vol 7, Issue 502.

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Abstract

Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.

Item Type: Article
Subjects: QV Pharmacology > QV 4 General works
W General Medicine. Health Professions > W 20.5 Biomedical research
WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases
WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
WH Hemic and Lymphatic Systems > Lymphatic System > WH 650 Reticuloendothelial system
Faculty: Department: Biological Sciences > Parasitology Department
Digital Object Identifer (DOI): https://doi.org/10.1038/s41598-017-00529-6
Depositing User: Stacy Murtagh
Date Deposited: 05 Apr 2017 10:05
Last Modified: 06 Feb 2018 13:14
URI: http://archive.lstmed.ac.uk/id/eprint/6915

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