title: Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.
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.
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Aljayyoussi
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Jenkins
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Ardrey
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Donnellan
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK. Giancarlo.biagini@lstmed.ac.uk.
authors.forename: Giancarlo A
authors.identifier: 0000-0001-6356-6595
authors.initials: GA
authors.lastname: Biagini
mesh_terms: D000465:Algorithms; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D050296:Microbial Viability / Q000187:drug effects; D008962:Models, Theoretical; D009010:Monte Carlo Method; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents