DDMoRe Model Repository

Short description:

The multistate tuberculosis pharmacometric (MTP) model describes the in vitro natural growth of Mycobacterium tuberculosis. The model consists of a three-compartment differential equation system representing fast-, slow- and non-multiplying tuberculosis bacteria.

Format:	Original code
Related Publication:	A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro Oskar Clewe, Linda Aulin, Yanmin Hu, Anthony Coates, Ulrika SH Simonsson Journal of Antimicrobial Chemotherapy, 4/2016, Volume 71, Issue 4, pages: 964-74 Affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Abstract: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states. The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships. The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2)?=?0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively. The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.
Contributors:	Oskar Clewe

Context of model development:	Mechanistic Understanding;
Model compliance with original publication:	Yes;
Model implementation requiring submitter’s additional knowledge:	No;
Modelling context description:	Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.;
Modelling task in scope:	estimation;
Nature of research:	In vitro;
Therapeutic/disease area:	Anti-infectives;

Validation Status:	Annotations are correct.
Certification Comment:	This model is not certified.

DDMODEL00000240: The Multistate Tuberculosis Pharmacometric model

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