Research & Projects
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- Systems pharmacology-based translational framework for tuberculosis
- Model-based analysis of tuberculosis biomarkers
- Non-linear mixed-effects modeling of rifapentine PK and PD
The long-term goal in this project is to develop a general translational system pharmacology simulation framework to help evaluate new treatment intervention hypotheses from novel findings in basic and preclinical research for testing in small, focused tuberculosis (TB) clinical trials. The solution will combine multi-level systems biology and population PK-PD approaches to predict response of multi-drug treatment. The work will explore genetic factors, host- and drug-interactions driving disease evolution, bacterial adaptation, and infection response to therapy.
The project aims to:
- develop a unified system pharmacology framework.
- explore networks of proteins, cells, and other potential biomarkers driving variability in clinical response.
- develop hypotheses for innovative dosing strategies to provide optimal drug therapy in patients, which may later be tested in focused, small-scale clinical trials.
We apply a model-based analysis to support the identification of M. tuberculosis biomarkers for diagnosis and cure, such as MGIT and Xpert, in order to determine their correlation to bacterial load or treatment response. The overall objective of the analysis is to assess biomarker–treatment response/bacterial load relationship after oral administration of standard of care treatment in pulmonary tuberculosis patients by means of non-linear mixed effects modeling.
We apply nonlinear mixed effects modeling to study rifapentine’s pharmacokinetics and pharmacodynamics, particularly, to characterization PK and clinical predictors of poor outcome. We also evaluate the relationships between rifapentine plasma concentration and other predictors, on the magnitude of rifapentine autoinduction of clearance.
Area under the curve of rifapentine for pediatric vs. adult patients. Weiner, Savic et al., Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection, J Pediatric Infect Dis Soc 2014:3 (2),132–45