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

Abstract

AbstractBackgroundQuantitative systems pharmacology (QSP) modeling of the host-immune response against Mtb can inform 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.MethodsA QSP framework for autophagy was developed by extending a model for host-immune response to include AMPK-mTOR-autophagy signalling. This model was combined with pharmacokinetic-pharmacodynamic models for metformin and antibiotics against Mtb. We compared the model predictions to mice infection experiments, and derived predictions for pathogen and host-associated dynamics in humans treated with metformin in combination with antibiotics.ResultsThe model adequately captured the observed bacterial load dynamics in mice Mtb infection models treated with metformin. Simulations for adjunctive metformin therapy in newly diagnosed patients suggested a limited yet dose-dependent effect of metformin on reducing the intracellular bacterial load and selected pro-inflammatory cytokines. Our predictions suggest that metformin may provide beneficiary effects when overall bacterial load, or extracellular-to-intracellular bacterial ratio is low, either early after infection or late during antibiotic treatment.ConclusionsWe present the first QSP framework for HDTs against Mtb, linking cellular-level autophagy effects to disease progression. This framework may be extended to guide design of HDTs against Mtb.