关键词: 结核, 预防和防护用药, 利福霉素类, 异烟肼, 药代动力学

Abstract:

Objective To evaluate the pharmacokinetic characteristics of rifapentine combined with isoniazid therapy (3HP for 3 months, once a week) for tuberculosis prevention in silicotic patients. Methods A total of 25 silicosis patients treated with 3HP regimen and pharmacokinetic monitoring in the First People's Hospital of Wenling City, Zhejiang Province from May 2015 to June 2018 were selected as the research subjects. At 8 weeks after the initiation of treatment, before taking the drug, the patients should stayed overnight (more than 10 h) without any food, peripheral venous blood was collected in limosis the next morning (0 h before taking the drug), and at 2, 4, 5, 6, 8, 12, 24, and 72 h after taking the drug. The plasma concentrations of isoniazid, rifapentine and their metabolites were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were obtained by analyzing the plasma concentration data using DAS 2.0 software. Results The pharmacokinetic parameters (M (Q₁, Q₃)) of isoniazid and theacetyl metabolite were as follows: AUC_(0-t), 14.1 (10.3, 22.2) and 7.6 (6.3, 8.4) μg·h/ml; AUC_(0-∞), 14.3 (10.7, 22.4) and 8.0 (7.2, 9.2) μg·h/ml; t_1/2, 1.6 (1.3, 1.8) and 6.0 (5.2, 7.9) h; t_max, 2.0 (2.0, 4.0) and 2.0 (2.0, 4.5) h; C_max, 3.7 (2.4, 5.5) and 6.6 (5.5, 9.8) μg/ml. And the main pharmacokinetic parameters (M (Q₁, Q₃)) of rifapentine and the active 25-desacetyl metabolite were as follows: AUC_(0-t), 919.6 (742.3, 1113.1) and 660.1 (517.6, 739.8) μg·h/ml; AUC_(0-∞), 1035.4 (758.2, 1191.3) and 913.4 (685.7, 1097.3) μg·h/ml; t_1/2, 18.3 (14.5, 21.6) and 32.3 (22.1, 46.3) h; t_max, 8.0 (7.0, 12.0) and 24.0 (18.0, 24.0) h; C_max, 32.2 (28.6, 37.7) and 15.1 (11.2, 18.2) μg/ml. All the subjects were followed up until 1 month after the completion of medication, of them, 14 cases (56.0%) had adverse drug reactions. Conclusion When the 3HP regimen was applied to prevent tuberculosis in silicotic patients, the metabolism of isoniazid was faster, while the metabolism of rifapentin was slower, which may be related to the occurrence of more adverse drug reactions in patients.

Key words: Tuberculosis, Protective agents, Rifamycins, Isoniazid, Pharmacokinetics