Population Pharmacokinetics and Dosing Optimization of Vancomycin in Pediatric Liver Transplant Recipients.
Population Pharmacokinetics and Dosing Optimization of Vancomycin in Pediatric Liver Transplant Recipients.
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DOI：
10.1128/spectrum.00460-21
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发表时间：
2021-10-31
影响因子：
3.7
通讯作者：
Miyairi I
中科院分区：
文献类型：
--
作者：
Shoji K;Saito J;Nakagawa H;Funaki T;Fukuda A;Sakamoto S;Kasahara M;Momper JD;Capparelli EV;Miyairi I
耐甲氧西林金黄色葡萄球菌感染是儿童肝移植 (LT) 受者发病和死亡的一个重要原因。 LT 后的生理变化可能会影响万古霉素的药代动力学；然而，尚无儿童 LT 接受者通过适当剂量达到足够药物暴露（即 24 小时浓度-时间曲线下面积 [AUC24]/MIC ≥ 400）的报道。这项针对 18 岁以下 LT 接受者的回顾性药代动力学研究利用了从电子病历中获得的万古霉素浓度和剂量信息的患者特征数据。使用 Phoenix NLME 软件通过非线性混合效应模型进行群体药代动力学分析。通过单变量和多变量分析筛选潜在的协变量。使用最终模型进行蒙特卡罗模拟以探索适当的剂量。该研究包括 270 个药代动力学特征，涵盖 161 名患者测量的 1,158 个浓度。中位年龄为 13.3 个月（四分位距，7.6 至 53.5）个月，血清肌酐 (sCr) 为 0.16（0.12 至 0.23）mg/dl，自 LT 起的天数（DFLT）为 17 天（6 至 31）。多变量分析表明，较低的 sCr 和较短的 DFLT 与较高的清除率相关。根据事后估计，平均清除率和分布体积分别为 0.18 升/小时/千克和 1.01 升/千克。蒙特卡罗模拟显示，只有 16% 的患者达到 AUC24/MIC ≥400，假设万古霉素 MIC 为 1μg/ml。 DFLT 和 sCr 是儿科 LT 接受者万古霉素清除率的显着协变量。标准万古霉素剂量可能不足，并且肾功能正常的儿科 LT 接受者可能需要更高或更频繁的剂量才能达到≥400 的 AUC24/MIC。重要性 我们评估了儿科 LT 接受者的万古霉素药代动力学，并通过考虑可能解释万古霉素药代动力学改变的各种因素，开发了群体药代动力学模型。我们的分析显示，较低的血清肌酐水平和自 LT 之日起较短的持续时间与较高的万古霉素清除率相关，并导致亚治疗药物暴露。我们还进行了蒙特卡罗模拟以确定儿童 LT 接受者的适当剂量策略，结果表明标准万古霉素剂量可能不足，并且可能需要更高或更频繁的给药才能在肾功能正常的儿童 LT 接受者中实现 ≥ 400 的 AUC24/MIC。据我们所知，这是第一项通过群体药代动力学分析评估万古霉素在儿科 LT 接受者中药代动力学的研究。
Methicillin-resistant Staphylococcus aureus infections are a significant cause of morbidity and mortality in pediatric liver transplant (LT) recipients. Physiological changes following LT may affect vancomycin pharmacokinetics; however, appropriate dosing to achieve sufficient drug exposure (i.e., 24-h area under the concentration-time curve [AUC24]/MIC ≥ 400) in pediatric LT recipients has not been reported. This retrospective pharmacokinetics study of LT recipients aged <18 years utilized data on patient characteristics with vancomycin concentrations and dosing information obtained from electronic medical records. Population pharmacokinetics analysis was conducted by nonlinear mixed-effects modeling with the Phoenix NLME software. Potential covariates were screened with univariate and multivariate analysis. Monte Carlo simulations were performed using the final model to explore appropriate dosing. The study included 270 pharmacokinetics profiles encompassing 1,158 concentrations measured in 161 patients. The median age was 13.3 (interquartile range, 7.6 to 53.5) months, serum creatinine (sCr) was 0.16 (0.12 to 0.23) mg/dl, and days from LT (DFLT) was 17 (6 to 31). Multivariate analysis demonstrated that lower sCr and shorter DFLT were associated with higher clearance. By post hoc estimation, the average clearance and volume of distribution were 0.18 liters/h/kg and 1.01 liters/kg, respectively. The Monte Carlo simulations revealed that only 16% of patients achieved an AUC24/MIC of ≥400 with the assumed vancomycin MIC of 1 μg/ml. DFLT and sCr were significant covariates for vancomycin clearance in pediatric LT recipients. Standard vancomycin dosing may be insufficient, and higher or more frequent dosing may be required to achieve an AUC24/MIC of ≥400 in pediatric LT recipients with normal renal function. IMPORTANCE We evaluated vancomycin pharmacokinetics in pediatric LT recipients and developed a population pharmacokinetics model by considering various factors that might account for alterations in vancomycin pharmacokinetics. Our analyses revealed that lower serum creatinine levels and a shorter duration from the day of LT were associated with higher vancomycin clearance and led to subtherapeutic drug exposure. We also performed Monte Carlo simulations to determine the appropriate dosing strategy in pediatric LT recipients, which revealed that a standard vancomycin dosing might be insufficient and that higher or more frequent dosing might be necessary to achieve an AUC24/MIC of ≥400 in pediatric LT recipients with normal renal function. To the best of our knowledge, this is the first study to assess vancomycin pharmacokinetics in pediatric LT recipients by population pharmacokinetics analysis.