Modeling & Simulation Workgroup Q3-2015 Update
Working closely with the Data Standards and Integration Workgroup (DSI-WG), the M&S-WG uses aggregated clinical trial data to create robust empirical, mechanistic, and systems biology models and quantitative simulation tools to facilitate TB drug and drug regimen development.
- A number of critical translational gaps exist in the science of TB drug regimen development. The M&S-WG is comprised of multiple partnerships designed to develop models that address some of the current limitations in TB combination drug development.
- The PBPK model of the TB-infected lung has been updated to include linking the TB growth model to the lung PK model in Simulink and adding in the effect of drugs (in combination) on the bacteria. Modeling of the PK effects in the lung using the new pretomanid and bedaquline data is progressing.
The first stage of experimental studies with the HFS-TB model, focusing on evaluation of REMox under log phase, acidic, and intracellular growth conditions completed June 30, 2015. The HFS-TB data met the go/no-go criteria as defined. The second stage of experimental studies will be defined by the expert team.
- Inclusion of imaging modalities as part of Mechanism-Based Integrative Pharmacology model was completed ahead of schedule. This model will be used to integrate with other efforts, such as the Liquid Culture Modeling and Hollow Fiber Systems, to scale into a comprehensive clinical trials simulation tool that optimizes clinical trial design for Phase II and Phase III studies.
- Data access to the FDA-funded study of electrophysiological effects of known QT-prolonging drugs, led by Strauss et al., was received. Additional QT studies for moxifloxacin are being pursued and summary-level data from these data sets are being modeled.
- Development of the Liquid Culture model, based on Phase II data, was completed on schedule. The addition of a baseline severity covariate and an HIV co-infection covariate began. This model constitutes the main deliverable from the first stage of this project.
- For the population PK/PD modeling effort, data acquisition from the Tyler, Texas site completed ahead of schedule. Data acquisition from the Florida Department of Health (DOH) and the Texas Center for Infectious Diseases (TCID) are progressing. The data management effort is scheduled to complete in January, 2016.