Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Department of Infectious Diseases, University Hospital Linköping, Linköping, Sweden.
J Antimicrob Chemother. 2018 Oct 1;73(10):2838-2845. doi: 10.1093/jac/dky268.
Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs.
To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs.
Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (Chigh) were determined, as well as estimates of Chigh/MIC and area under the concentration-time curve (AUC0-6)/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261).
After 2 weeks of treatment, the median Chigh values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (<8 mg/L), 19% for isoniazid (<3 mg/L), 27% for pyrazinamide (<35 mg/L) and 16% for ethambutol (<2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC0-6/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid.
We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.
治疗药物监测（TDM）可以改善当前的结核病治疗，但很少有研究同时报告药代动力学数据和 MIC 值。
检测利福平、异烟肼、吡嗪酰胺和乙胺丁醇的血药浓度以及 MIC 值。
在 31 例结核病患者中，于第 2 周服药前和服药后 2、4 和 6 小时采集利福平、异烟肼、吡嗪酰胺和乙胺丁醇的药物浓度，并在基线时使用 BACTEC 960 MGIT 测定 MIC 值。确定最高血药浓度（Chigh）和药时曲线下面积（AUC0-6）/MIC 比值，包括基于游离药物浓度计算的相应比值。本试验在 www.clinicaltrials.gov（NCT02042261）上注册。
治疗 2 周后，利福平、异烟肼、吡嗪酰胺和乙胺丁醇的中位 Chigh 值分别为 10.0、5.3、41.1 和 3.3mg/L。42%的患者利福平（<8mg/L）、19%的患者异烟肼（<3mg/L）、27%的患者吡嗪酰胺（<35mg/L）和 16%的患者乙胺丁醇（<2mg/L）低于推荐的药物浓度。利福平、异烟肼、吡嗪酰胺和乙胺丁醇的 Chigh/MIC 值中位数分别为 164、128、1.3 和 2.5，AUC0-6/MIC 值分别为 636（范围 156-2759）和 351（范围 72-895）。
我们报告了 16%-42%的患者存在一线结核病药物水平低的情况，特别是利福平。药物暴露与 MIC 之间的比值分布广泛。未来 TDM 中 MIC 测定的应用取决于参考方法的开发和经临床验证的药代动力学/药效学靶值。
