Fage David, Brilleman Reda, Deprez Guillaume, Payen Marie-Christine, Cotton Frédéric
Department of Clinical Chemistry, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.
Université Libre de Bruxelles, Brussels, Belgium.
J Pharm Biomed Anal. 2022 Jun 5;215:114776. doi: 10.1016/j.jpba.2022.114776. Epub 2022 Apr 19.
The treatment of tuberculosis, in particular the multi-drug resistant tuberculosis, remains a challenge mainly because of the therapy duration and the pharmacokinetic variability of the drugs included in the regimen. The monitoring of antituberculosis drugs is a recent tool that could improve the outcome of patients. We developed a LC-MS/MS method allowing the simultaneous quantification of the four first-line drugs (isoniazid, rifampicin, pyrazinamide and ethambutol), a metabolite of isoniazid (acetylisoniazid) and the five main second-line drugs (rifabutin, levofloxacin, moxifloxacin, linezolid and bedaquiline). An isotopologue standard was used for each drug. The protein precipitation was performed with acetonitrile and the separation was carried out using an EC-18 column and a gradient elution. The validated ranges for each drug were adapted to monitor the plasma concentration at 2 h (peak) and 6 h to evaluate their enteric absorption. The intermediate precision (CV) and the trueness at the limit of quantification were ≤ 10.1% and ≤ 10.7%, respectively. Preliminary data were obtained for 12 patients. The results showed that 38% of the patients had infra-therapeutic levels for both rifampicin and isoniazid, that the leading cause of an impaired oral absorption seemed to be malabsorption and that the effective concentrations for rifampicin were in the lower range of the therapeutic interval.
结核病的治疗，尤其是耐多药结核病的治疗，仍然是一项挑战，主要原因在于治疗疗程以及治疗方案中所包含药物的药代动力学变异性。对抗结核药物进行监测是一种新近出现的有助于改善患者治疗效果的手段。我们开发了一种液相色谱-串联质谱法，可同时定量测定四种一线药物（异烟肼、利福平、吡嗪酰胺和乙胺丁醇）、异烟肼的一种代谢物（乙酰异烟肼）以及五种主要的二线药物（利福布汀、左氧氟沙星、莫西沙星、利奈唑胺和贝达喹啉）。每种药物均使用了一种同位素内标物。采用乙腈进行蛋白沉淀，并使用EC-18柱和梯度洗脱进行分离。每种药物的验证范围适用于监测2小时（峰值）和6小时的血浆浓度，以评估它们的肠道吸收情况。定量限处的中间精密度（CV）和准确性分别≤10.1%和≤10.7%。获得了12例患者的初步数据。结果显示，38%的患者利福平和异烟肼的血药浓度低于治疗水平，口服吸收受损的主要原因似乎是吸收不良，且利福平的有效浓度处于治疗区间的较低范围。
