Modeling & Simulation Workgroup (M&S-WG) Q4-2015 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.
Many critical translational gaps exist in the science of TB drug regimen development. The Modeling and Simulation Workgroup is comprised of multiple partnerships designed to develop models that address some of the current limitations in TB combination drug development. For a complete list of objectives, see Appendix A.
4Q, 2015 Progress:
- M&S planning for the CPTR Annual Meeting is complete: speakers, topics, and poster sessions are confirmed.
- The PBPK Model to understand the drug distribution from the systemic blood into the different compartments of the lung is fully operational within the Simcyp simulator environment.
- The Simcyp team linked the TB growth model to the lung PK model in Simulink and incorporated the effect of drugs (in combination) on bacteria. The model now incorporates a granuloma compartment. The model now simulates different concentration dynamics for drug penetration into and within the granuloma. Simcyp will deliver a training workshop in 2Q, 2016.
- Modeling the Population PK and penetration of first and second line anti-TB drugs in pulmonary lesions from adults with active tuberculosis complete.
- The University of Florida team completed integrating imaging modalities into this model ahead of schedule. This benchmark serves as a foundation for the cross-fertilization with other modeling efforts, such as the Liquid Culture Empirical Modeling and HFS-TB
- The UC San Francisco team completed the development of the Liquid Culture model, based on Phase II data, on schedule. It includes the following:
- The addition of a baseline severity covariate and an HIV co-infection.
- Possible acceleration of TTP trajectories using a Gompertz function.
- Modeled the TTP curve as bi-modal as a role of an immune system “kicking in” or the killing of certain bacteria populations.
- CPTR completed a draft outline for a statement of work describing the HFS-TB stage 2 experimental studies.
- Pharsight has received the data from the FDA-funded study of electrophysiological effects of known QT-prolonging drugs, led by Strauss et al. The team is currently on schedule to validate the 12 test drugs and simulate the single drug and combination drugs. The final report (1Q, 2016) will include results.
- CPTR and the WHO launched a new program in partnership to conduct a model-based meta-analysis of endpoints analyzed in the REMox, Oflotub and Rifaquin Phase III studies. The steering committee has been established and the specific aims are being finalized. Work will commence with Dr. Rada Savic (UCSF) in March, 2016.