A Physiologically-Based Pharmacokinetic Model for Tuberculosis Drug Disposition at Extrapulmonary Sites

Tuberculosis (TB) is a leading cause of mortality due to an infectious agent. TB primarily targets the lungs but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. While the recommended treatment for most forms of EPTB is the same as pulmonary TB, pharmacokinetics of EPTB therapy are not as well-studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the 4 first-line anti-TB drugs: Rifampicin, Ethambutol, Isoniazid and Pyrazinamide. We utilise reported plasma concentration kinetics data to estimate model parameters for each drug, and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data and reported PK parameters ( Cmax, tmax ) for the drugs. The model also predicts Ethambutol, Isoniazid and Pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the model is used to simulate the time-dependent drug concentrations at various EPTB sites. Predicted drug concentrations are compared to their critical concentration. Simulations suggest that while Rifampicin and Isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of Ethambutol and Pyrazinamide are lower than their critical concentrations at most EPTB sites.