A physiologically-based pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites

Abstract

Tuberculosis (TB) is a leading cause of mortality attributed 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. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the 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, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use 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 pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) 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 predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although 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.

FIGURE 1

Schematic diagram of the whole‐body physiologically‐based pharmacokinetic model incorporating pleura and lymph node compartments (highlighted). Blood flows to an organ/tissue T with a flow rate Q_T and leaves with a flow rate Q_T – L_T, where L_T is the lymph flow rate from T. The drug is administered orally. CL_R (= f_R x CL, where CL is the systemic clearance) and CL_H (= (1 − f_R) x CL) represent renal and hepatic clearance, respectively.

FIGURE 2

Model‐predicted plasma concentrations for oral doses of rifampicin (450 mg), ethambutol (400 mg), isoniazid (300 mg), and pyrazinamide (2000 mg) were fitted to reported plasma concentration data for each to estimate drug pharmacokinetic parameters. The parameters are listed in Tables S2–S6 in Appendix S1. The predicted PK parameters are listed in Table S7 in Appendix S1. FA, fast acetylator; SA, slow acetylator. Etb‐91‐1400B and Et‐ref‐400 are specific ethambutol products used by Strauch et al. in their study.

FIGURE 3

Simulated plasma concentrations for oral doses of rifampicin (600 mg), ethambutol (1200 mg), isoniazid (300 mg), and pyrazinamide (1500 mg) plotted along with reported plasma concentration data for each drug dose. The model parameters used are listed in Appendix S1. Data used for calibration were not used for model validation. FA, fast acetylator; SA, slow acetylator.

FIGURE 4

Simulated pleura drug concentrations for oral doses of rifampicin (600 mg), ethambutol (1200 mg), isoniazid (300 mg), and pyrazinamide (1500 mg) plotted along with reported concentration data for each drug dose. The model parameters used are listed in Appendix S1. The gray dashed line represents the critical concentration of each drug. Day 8 simulations are used for all drugs except ethambutol for which Day 2 concentrations corresponding to the experimental data are simulated. FA, fast acetylator; SA, slow acetylator; CC, critical concentration.

FIGURE 5

Simulated lung tissue drug concentrations for oral doses of rifampicin (600 mg), ethambutol (1200 mg), isoniazid (300 mg), and pyrazinamide (1500 mg) plotted along with reported concentration data for each drug dose. Day 1 concentrations are simulated for rifampicin, isoniazid, and pyrazinamide and compared with the study by Prideaux et al. Day 7 concentrations for ethambutol are simulated as the reported data they are compared with correspond to long‐term drug concentrations in the tissue after daily administration. The model parameters used are listed in Appendix S1. The gray dashed line represents the critical concentration of each drug. FA, fast acetylator; SA, slow acetylator; CC, critical concentration.

FIGURE 6

Simulated Day 7 drug concentrations at various sites of extrapulmonary tuberculosis for recommended oral doses of rifampicin (600 mg), ethambutol (1200 mg), isoniazid (300 mg), and pyrazinamide (1600 mg) compared with the critical concentration of each drug. The same parameter values from model calibration are used here. FA, fast acetylator; SA, slow acetylator; CC, critical concentration.