Abstract:

Objective To establish hollow-fiber pharmacodynamic model of tuberculosis(HFM-TB) for the pharmacokinetics/pharmacodynamics (PK/PD) study in vitro, and the method will be used to obtain the isoniazid PK/PD parameters, the HFM-TB provides a tool for the PK/PD study of new drugs in vitro. Methods The hollow fiber system was assembled, and the H37Rv strain in the logarithmic phase of growth was inoculated into the outer comparment of the hollow fiber culture tube at a concentration of 1×10 ⁶ colony forming units (CFU)/ml for a total of 15 ml. The concentration-time distribution of isoniazid in the system were simulated in human patients at doses of 25, 50, 150, 300 and 1200 mg/d, Samples were taken at 0.5, 1, 3.5, 6.5, 9.5,13, 24, 24.5, 25, 27.5, 30.5, 33.5, 37 and 48 h,after administration. The concentrations of isoniazid were determined by high-performance liquid chromatographic (HPLC). The total bacteria load and isoniazid resistance in the system were monitored through the samples taken from the outer compartment of the culture tube daily for 7 days after administration. The PK/PD parameters were calculated by PKSolver plug-in. Results In the HFM-TB, isoniazid showed significant early bactericidal activity on the first day of administration, while the time when the bactericidal effect ceased was 3-5 days after administration. After 7 days of administration, the proportion of drug-resistant TB at the 50-1200 mg/d dose group accounted for ≥39% of all. AUC_0-24/MIC was the best fitting effect of PK/PD parameters for isoniazid. The maximum effect (E_max) was 3.02 CFU/ml, and EC₅₀ reached when AUC_0-24/MIC=52.23, after 2 days of administration. Conclusion The HFM-TB was successfully established in China for the first time. AUC_0-24/MIC is the target PK/PD parameter of isoniazid for H37Rv.

Key words: Mycobacterium tuberculosis, Pharmacokinetics/Pharmacodynamics, Isoniazid, In vitro