Development of a Novel Multi-compartment Granuloma Model to Predict Local Drug Distribution and Its Impact on Pharmacodynamics and Disease Progression in Tuberculosis

Author(s): Rachel Rose, Gaohua Lu, Janak Wedagedera, Ben Small, Adrian Barnett, Klaus Romero, David Hermann, Iain Gardner, Masoud Jamei

Objectives: One of the hallmarks of pulmonary tuberculosis (TB) is the formation of granulomas, heterogeneous lesions composed of macrophage and neutrophil rich peripheral regions and a necrotic core, in the lungs of the infected host. Anti-TB drugs must penetrate these lesions to exert their effects. This work aimed to extend a permeability-limited lung model [1] to describe drug disposition within a tuberculosis granuloma and to incorporate a disease progression model that describes the growth of the granuloma and the pharmacodynamic effect of locally-acting drugs on bacteria located within different lesions of the granuloma.

Methods: A permeability-limited lung model was extended with the addition of a novel multi-compartment granuloma model consisting of three layers: the well vascularized cellular rim, the outer caseum and the inner caseum compartments. The rim was further sub-divided into mass, interstitial fluid (ISF) and blood compartments. Granuloma growth and disease progression in active and latent tuberculosis was modeled based on work published previously [2]. The volume of the rim mass compartment was defined by the total number of macrophages from the disease progression model and drug effects are incorporated as a local concentration dependent kill rate for bacteria localized to different compartments of the granuloma. The model has been implemented in Simcyp V16, with the disease progression model implemented via a Lua script to allow the user the flexibility to customize the model.

Results: Local free drug concentration within different granuloma compartments is dependent on the interplay between several factors including free drug concentration in the plasma and lung tissue of the simulated individual, active transport and passive permeability between granuloma compartments and binding within different compartments of the granuloma model. Local free drug concentration significantly impacts on the rate of killing of bacteria within different granuloma compartments and hence the predicted response to treatment.

Conclusions: The multi-compartment granuloma model provides a framework for investigating the impact of inter-individual variability in drug pharmacokinetics and local drug concentration on the killing of M. tuberculosis sub-populations. Ongoing work aims to validate the model predictions for anti-TB drugs and treatment regimens.

[1] Gaohua L, Wedagedera J, Small BG, Almond L, Romero K, Hermann D, Hanna D, Jamei M, Gardner I. Development of a multicompartment permeability-limited lung PBPK model and its application in predicting pulmonary pharmacokinetics of antituberculosis drugs. CPT Pharmacometrics Syst Pharmacol (2015) 4(10):605-13
[2] Sud D, Bigbee C, Flynn JL and Kirschner DE. Contribution of CD8+ T cells to control of Mycobacterium tuberculosis infection. J Immunol (2006) 176:4296-314

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