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

Aljayyoussi, Ghaith; Jenkins, Victoria A.; Sharma, Raman; Ardrey, Alison; Donnellan, Samantha; Ward, Stephen A.; Biagini, Giancarlo A.

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.

Citation

Aljayyoussi, G., Jenkins, V. A., Sharma, R., Ardrey, A., Donnellan, S., Ward, S. A., & Biagini, G. A. (2017). Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration. Scientific Reports, 7(1), Article 502 (2017). https://doi.org/10.1038/s41598-017-00529-6

• Journal Article Type: Article
• Acceptance Date: Mar 1, 2017
• Online Publication Date: Mar 29, 2017
• Publication Date: 2017
• Deposit Date: Feb 11, 2021
• Publicly Available Date: Feb 11, 2021
• Journal: Scientific Reports
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 1
• Article Number: 502 (2017)
• DOI: https://doi.org/10.1038/s41598-017-00529-6
• Public URL: http://researchrepository.napier.ac.uk/Output/2718415