Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India.
Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India.
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DOI：
10.3389/fphar.2022.1081123
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发表时间：
2022
影响因子：
5.6
通讯作者：
Tornheim, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Resendiz-Galvan, Juan Eduardo;Arora, Prerna R.;Abdelwahab, Mahmoud Tareq;Udwadia, Zarir F.;Rodrigues, Camilla;Gupta, Amita;Denti, Paolo;Ashavaid, Tester F.;Tornheim, Jeffrey A.
利奈唑胺是一种恶唑烷酮，用于治疗耐多药结核病(MDR-TB)，包括最近批准的较短的6个月治疗方案。由于其狭窄的治疗指数，利奈唑胺在治疗过程中往往要么调整剂量，要么由于不耐受或毒性而停用，利奈唑胺疗效和毒性之间的最佳平衡尚不清楚。印度的耐多药结核病病例在世界上负担很大，但印度耐多药结核病患者提供的关于利奈唑胺的药代动力学和最低抑菌浓度分布的信息有限。我们从印度孟买的一家三级护理中心招募了参与者，他们接受耐多药结核病的治疗，每天接受600或300毫克的利奈唑胺治疗。药物动力学检查计划在治疗开始后1至15个月内进行，以进行密集或稀疏的血液采样。使用非线性混合效应模型分析利奈唑胺浓度与时间的关系数据，并通过模拟评估不同情况下的剂量。我们招募了183名参与者(121名女性)，中位年龄26岁(四分位数范围21-35)，体重55.0公斤(IQR 45.6-65.8)，脱脂体重38.7公斤(IQR 32.7-46.0)。利奈唑胺的药代动力学符合一室模型，一级消除由脱脂质量和转运室吸收决定。典型的清除值为3.81MIC L/小时。模拟预测，当利奈唑胺的最低抑菌浓度为0.25MIC/L(61.5%的受试者样本)时，每天服用300亿毫克的药物可获得很高的靶向达标率(≤)，而如果MIC为0.5%/L(29%的样本)，则每天需要600百万毫克。虽然利奈唑胺每天300 mg被预测可以达到大多数耐多药结核病成年人的有效目标，但它未能达到21%参与者的治疗目标。600毫克剂量对所有敏感样本的PTA和GT；都是90%，但超过毒性阈值的可能性更高(31%比9.6%)。这些数据表明，考虑到宿主和微生物的特点，个体化给药具有潜在的好处，以提高治疗疗效的可能性，同时将利奈唑胺治疗耐多药结核病的毒性风险降至最低。迫切需要在不同的临床环境中进行进一步的前瞻性评估，以告知这些较低剂量的安全性和有效性。
Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including in the recently-endorsed shorter 6-month treatment regimens. Due to its narrow therapeutic index, linezolid is often either dose-adjusted or discontinued due to intolerance or toxicity during treatment, and the optimal balance between linezolid efficacy and toxicity remains unclear. India carries a significant burden of MDR-TB cases in the world, but limited information on the pharmacokinetics of linezolid and minimum inhibitory concentration (MIC) distribution is available from Indian MDR-TB patients. We enrolled participants from a tertiary care centre in Mumbai, India, treated for MDR-TB and receiving linezolid daily doses of 600 or 300 mg. Pharmacokinetic visits were scheduled between 1 and 15 months after treatment initiation to undergo intensive or sparse blood sampling. Linezolid concentration versus time data were analysed using non-linear mixed-effects modelling, with simulations to evaluate doses for different scenarios. We enrolled 183 participants (121 females), with a median age of 26 years (interquartile range [IQR] 21–35), weight 55.0 kg (IQR 45.6–65.8), and fat-free mass 38.7 kg (IQR 32.7–46.0). Linezolid pharmacokinetics was best described by a one-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption. The typical clearance value was 3.81 L/h. Simulations predicted that treatment with 300 mg daily achieves a high probability of target attainment (PTA) when linezolid MIC was ≤0.25 mg/L (61.5% of participant samples tested), while 600 mg daily would be required if MIC were 0.5 mg/L (29% of samples). While linezolid 300 mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600 mg had a PTA >90% for all susceptible samples, but with a higher likelihood of exceeding toxicity thresholds (31% vs 9.6%). These data suggest potential benefit to individualized dosing taking host and microbial characteristics into account to improve the likelihood of treatment efficacy while minimizing risk of toxicity from linezolid for the treatment of MDR-TB. Further prospective evaluation in different clinical settings is urgently needed to inform safety and efficacy of these lower doses.
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影响因子：
158.5
作者：
Conradie, Francesca;Diacon, Andreas H.;Spigelman, Melvin
通讯作者：
Spigelman, Melvin
影响因子：
5.2
作者：
Livermore, DM
通讯作者：
Livermore, DM
贝达喹啉-Pretomanid-利奈唑胺治疗耐药结核病的方案。
DOI：
10.1056/nejmoa2119430
发表时间：
2022-09-01
期刊：
The New England journal of medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.6
作者：
Keizer, Ron J;Jansen, Robert S;Rosing, Hilde;Thijssen, Bas;Beijnen, Jos H;Schellens, Jan H M;Huitema, Alwin D R
通讯作者：
Huitema, Alwin D R
影响因子：
4.9
作者：
Diacon, A. H.;Patientia, R. F.;Donald, P. R.
通讯作者：
Donald, P. R.