The prolonged treatment duration for multidrug-resistant tuberculosis (MDR-TB) makes linezolid dosing difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid across different MIC values. Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used an fAUC (area under the unbound drug concentration-time curve)/MIC ratio of >119 as the PK/pharmacodynamic (PD) target and minimum (trough) concentrations of drug (C_mins) of 2 and 7 mg/liter as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%. A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kg. Eighty-one percent had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/liter for a total daily dose of 300 mg, while daily doses of 450 to 600 mg and 900 to 1,200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/liter, respectively. The probability of achieving a C_min of ≤2 mg/liter was higher when the dose was given at once than when dividing it into 2 doses. Linezolid at a daily dose of 300 mg may not be optimal. We predicted an excellent and comparable efficacy of linezolid using total daily doses of 900 and 1,200 mg for MICs of ≤0.5 mg/liter but with the potential for more toxicity than with 600 mg daily. The increase in C_min was noticeable when the daily dose was divided and may incur greater toxicity.

中文翻译：

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利奈唑胺在结核病患者中的群体药代动力学：给药方案模拟和目标达成分析。

耐多药结核病（MDR-TB）的治疗时间延长，由于长期使用会产生不良反应，因此难以服用利奈唑胺。我们试图找到在不同MIC值范围内利奈唑胺的最佳给药方案。来自结核病患者的药代动力学（PK）数据来自巴西，乔治亚州和两个美国站点。进行了人口PK建模和仿真。我们使用f AUC（未结合药物浓度-时间曲线下的面积）/ MIC之比> 119作为PK /药效学（PD）目标和最低（谷值）药物浓度（C_分钟s）2和7 mg / L作为毒性阈值。PK / PD断点定义为达到目标概率> 90％的最高MIC。总共纳入104例肺结核患者，中位年龄和体重为37岁和60公斤。百分之八十一患有耐药结核病。PK数据最好用一室模型来描述。每日总剂量为300 mg时PK / PD临界点为0.125 mg / L，而每日剂量为450至600 mg和900至1,200 mg时PK / PD临界点分别为0.25和0.50 mg / L。达到C_分钟的概率≤2 mg / L的剂量一次给药要比分为2剂时更高。每日300 mg的利奈唑胺可能不是最佳选择。我们预测每日总剂量为900和1,200 mg的MIC≤0.5mg / l时，利奈唑胺具有极好的可比疗效，但比每天600 mg毒性更大。当每日剂量分开时，C _min的增加是明显的，并且可能引起更大的毒性。