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基于药代动力学和药效学模拟的利奈唑胺相关性血小板减少症定量风险评估。

Pharmacokinetic and pharmacodynamic simulation for the quantitative risk assessment of linezolid-associated thrombocytopenia.

机构信息

Department of Pharmacy, Shimane University Hospital, Izumo, Japan.

Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan.

出版信息

J Clin Pharm Ther. 2022 Dec;47(12):2041-2048. doi: 10.1111/jcpt.13747. Epub 2022 Jul 27.

Abstract

WHAT IS KNOWN AND OBJECTIVE

Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia.

METHODS

This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 μg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses.

RESULTS AND DISCUSSION

Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CL ) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non-thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918-28.831] and 4.712 [95% CI: 1.567-14.163]; odds ratio for safety target achievement rate: 0.060 [95% CI: 0.016-0.232] and 0.167 [95% CI: 0.056-0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non-thrombocytopenic groups, the safety target achievement rate was higher in the non-thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more. Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD-induced thrombocytopenia.

WHAT IS NEW AND CONCLUSION

The risk of LZD-induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation.

摘要

已知和目的

利奈唑胺(LZD)可能会导致血小板减少症,这可能导致治疗中断。在这项研究中,根据来自先前发表的两个模型的群体药代动力学(PK)参数来估计血液 LZD 谷浓度,以确定当血小板减少症风险较低时达到目标谷值的速度,并阐明其与血小板减少症发病的关系。

方法

本研究纳入了 2010 年 1 月至 2017 年 12 月期间在岛根大学医院住院接受 LZD 治疗至少 4 天的成年患者。在 LZD 给药前血小板计数下降至 70%以下的患者被归类为血小板减少症组。根据 Matsumoto 等人和 Sasaki 等人描述的群体 PK 模型计算患者 PK 参数,并分别将这些参数指定为 A 和 B。基于这些参数,使用每个患者的随机模拟计算达到 LZD 谷浓度<8μg/ml 的安全目标达成率。我们进一步通过单变量、多变量和接收者操作特征(ROC)分析,分析血小板减少症的发生与患者因素(包括安全目标达成率)之间的关系。

结果和讨论

对 77 名年龄 72±11 岁、体重 56.7±10.9kg、肌酐清除率(CL)为 60.5±47.2ml/min 和肝硬化患病率为 9.1%的患者进行了分析。所有患者均接受 LZD 每日两次 600mg 的剂量治疗,总疗程为 10.9±8.9 天。单变量分析显示,血小板减少症组和非血小板减少症组之间 LZD 治疗持续时间、血清肌酐、肌酐清除率、LZD 清除率和参数 A 和 B 的安全目标达成率存在显著差异(p<0.05)。对这些因素进行多变量分析,并结合 ROC 分析获得的截断值进行分层分析,结果表明 LZD 治疗持续时间和参数 A 和 B 的安全目标达成率是显著因素(LZD 治疗持续时间的优势比:7.436[95%置信区间(CI):1.918-28.831]和 4.712[95%CI:1.567-14.163];参数 A 和 B 的安全目标达成率的优势比:0.060[95%CI:0.016-0.232]和 0.167[95%CI:0.056-0.498])。当比较血小板减少症组和非血小板减少症组中 LZD 治疗患者的安全目标达成率时,LZD 治疗<10 天和治疗 10 天或更长时间的非血小板减少症组的安全目标达成率更高。因此,通过 PK/PD 模拟估计的安全目标达成率可能是评估 LZD 诱导血小板减少症风险的重要指标。

创新和结论

LZD 治疗持续时间增加可能导致 LZD 诱导的血小板减少症风险增加,可通过血液浓度模拟获得的安全目标达成率进行预测。

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