Quantitative Systems Pharmacology Modeling Framework of Autophagy in Tuberculosis: Application to Adjunctive Metformin Host-Directed Therapy.

ABSTRACT

Quantitative systems pharmacology (QSP) modeling of the host immune response against Mycobacterium tuberculosis can inform the rational design of host-directed therapies (HDTs). We aimed to develop a QSP framework to evaluate the effects of metformin-associated autophagy induction in combination with antibiotics. A QSP framework for autophagy was developed by extending a model for host immune response to include adenosine monophosphate-activated protein kinase (AMPK)-mTOR-autophagy signaling. This model was combined with pharmacokinetic-pharmacodynamic models for metformin and antibiotics against M. tuberculosis. We compared the model predictions to mice infection experiments and derived predictions for the pathogen- and host-associated dynamics in humans treated with metformin in combination with antibiotics. The model adequately captured the observed bacterial load dynamics in mice M. tuberculosis infection models treated with metformin. Simulations for adjunctive metformin therapy in newly diagnosed patients suggested a limited yet dose-dependent effect of metformin on reduction of the intracellular bacterial load when the overall bacterial load is low, late during antibiotic treatment. We present the first QSP framework for HDTs against M. tuberculosis, linking cellular-level autophagy effects to disease progression and adjunctive HDT treatment response. This framework may be extended to guide the design of HDTs against M. tuberculosis.