Distribution of drug exposure and pharmacokinetic/pharmacodynamic predictor of first-line anti-TB drugs in a Korean prospective cohort study

초록

Background and Aims Pharmacokinetics (PK) and pharmacodynamics (PD) of anti-tuberculosis (TB) drugs are considered the key to the optimization of TB treatment. However, few prospective studies have reported PK or PK/PD data with large sample size. We, therefore, investigated drug exposure of first-line anti-TB drugs along with MIC in a Korean TB cohort with around 2000 patients. Methods Plasma concentration of isoniazid (INH), rifam-pin (RIF), ethambutol (EMB), and pyrazinamide (PZA) were measured from the blood samples randomly taken after usually two weeks of treatment in 650-1000 patients of a Korean TB cohort. MICs were determined for around 250 patients at baseline. Maximum concentration (Cmax) and 0-to-24 hour area under the curve (AUC0-24) in the plasma and AUC0-24/MIC in the lung were determined using the nonlinear mixed-effects models we developed. For the prediction of AUC0-24/MIC in the lung, the lung to plasma free drug concentrations ratio was additionally considered. Results INH, RIF, EMB, and PZA each had the median Cmax of 4.83, 12.0, 1.55, and 28.6 mg/L. Patients who could not attain the recommended target value of Cmax were 5%for INH, 4% for RIF, 72% for EMB, and 3% for PZA. The median AUC0-24/MIC in the lung for INH, RIF, EMB, and PZA were 5193, 727, 59.1, and 14.2, respectively. Conclusion Distribution of drug exposure and PK/PD predictor of first-line anti-TB drugs in Korean TB patients were reported in this study. Only less than 5% of patients exhibited low drug exposure levels in those drugs, except for EMB.