Studying the Effects of Anti-Tuberculosis Drugs at Extrapulmonary Sites using a Physiology-based Pharmacokinetic Model

Tuberculosis (TB) is a major cause of mortality due to an infectious agent. Standard TB treatment is multidrug therapy with 4 drugs. While TB primarily affects the lungs, it can also affect other sites, giving rise to extrapulmonary TB (EPTB). EPTB constituted about 16% of the worldwide notifications in 2019. However, it continues to be overlooked and an optimal regimen for EPTB is not defined. The recommended treatment for most forms of EPTB is the same as pulmonary TB, but the studies these recommendations are based on are few in number. Attaining sufficient concentrations of anti-TB drugs at extrapulmonary sites, at the appropriate time and for the optimum duration is essential for efficient EPTB treatment. PBPK models can be used to study the concentration profiles of drugs at different sites. Although TB treatment entails multiple drugs, PBPK studies have focused on mono-drug therapy in the body, or multidrug therapy only in the lung. Here, we use a PBPK model for multiple anti-TB drugs to simulate their concentration-time profiles at EPTB sites. We use the simulations to understand the effect of dosing regimens on number of hours the drugs stay above their MIC at these sites.