Background Linezolid, an important component of rifampicin- and multidrug-resistant tuberculosis (RR/MDR-TB) treatment, is associated with treatment-limiting toxicities, including anemia. Patient-level and linezolid pharmacokinetic risk factors for anemia have not been well described in children treated for RR/MDR-TB. Methods We evaluated the pharmacokinetics of linezolid and longitudinal hemoglobin data to validate an existing population linezolid pharmacokinetic model. We assessed the impact of linezolid pharmacokinetics and the risk of developing anemia in a prospectively enrolled cohort of children. The validation of a previously published population pharmacokinetic linezolid model used nonlinear mixed effects modeling. A multivariable ordinal logistic regression model was built to predict the incidence of anemia. Results A total of 112 children, median age 7.2 (IQR: 2.2–16.3) years, were included from South Africa (n=87) and India (n=25). Of these, 24 children contributed new linezolid pharmacokinetic data. The population pharmacokinetic model which informs the currently recommended linezolid dosing in children (10-15 mg/kg) was validated with these additional new data. For every 1 g/dL lower baseline hemoglobin, the odds of developing grade 3 or 4 anemia increased by 2.64 (95% CI 1.98-3.62). For every 1 mg/L*h higher linezolid area under the concentration-time curve (AUC), the odds of developing a grade 3 or 4 anemia increased by 1.012 (95% CI 1.007-1.017). Conclusions These data taken together, confirm currently recommended linezolid doses in children. The risk of anemia in children should be carefully considered and monitored throughout. Initiating linezolid in children with low baseline hemoglobin increases the probability of experiencing grade 3 or 4 anemia.

中文翻译：

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利福平耐药结核病儿童利奈唑胺药代动力学-贫血建模


背景 利奈唑胺是利福平和耐多药结核病 （RR/MDR-TB） 治疗的重要组成部分，与包括贫血在内的限制性治疗毒性有关。在 RR/MDR-TB 接受治疗的儿童中，贫血的患者水平和利奈唑胺药代动力学危险因素尚未得到很好的描述。方法 我们评估了利奈唑胺的药代动力学和纵向血红蛋白数据，以验证现有的群体利奈唑胺药代动力学模型。我们评估了利奈唑胺药代动力学的影响和前瞻性入组儿童队列中发生贫血的风险。先前发表的群体药代动力学利奈唑胺模型的验证使用了非线性混合效应模型。构建多变量顺序 logistic 回归模型来预测贫血的发生率。结果 共纳入来自南非 （n=87） 和印度 （n=25） 的 112 名儿童，中位年龄 7.2 （IQR： 2.2-16.3） 岁。其中，24 名儿童贡献了新的利奈唑胺药代动力学数据。通过这些额外的新数据验证了告知目前推荐的儿童利奈唑胺剂量 （10-15 mg/kg） 的群体药代动力学模型。基线血红蛋白每降低 1 g/dL，发生 3 级或 4 级贫血的几率增加 2.64 （95% CI 1.98-3.62）。浓度-时间曲线 （AUC） 下利奈唑胺面积每升高 1 mg/L*h，发生 3 级或 4 级贫血的几率增加 1.012 （95% CI 1.007-1.017）。结论 这些数据综合起来，证实了目前推荐的儿童利奈唑胺剂量。应仔细考虑并全程监测儿童贫血的风险。在基线血红蛋白水平低的儿童中开始使用利奈唑胺会增加发生 3 级或 4 级贫血的可能性。