Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Pharmacotherapy. 2023 Dec;43(12):1262-1276. doi: 10.1002/phar.2865. Epub 2023 Aug 28.
Vancomycin dosing tailored for newborns is challenging due to the significant influence of maturation and organ function on pharmacokinetics. Population pharmacokinetic (popPK) models can be used to improve target attainment in neonates.
The primary objective was to derive and evaluate a popPK model of intravenous vancomycin for neonates. Second, the predictive performance of this popPK model was compared with published popPK models.
This is a retrospective cohort study of neonates admitted to the neonatal intensive care unit receiving intravenous vancomycin. A popPK model was derived with 70% of the dataset using a nonlinear mixed effects modeling method. The predictive performance of the current popPK model was validated and compared with 22 published popPK models using the remaining 30% of the dataset. Monte Carlo simulations (MCS) were performed to derive optimal dosing regimens to treat neonatal sepsis caused by coagulase-negative staphylococci (CoNS).
Among 655 vancomycin courses from 448 neonates, 78% of vancomycin trough concentrations were outside target range (10-15 mg/L) for central nervous system infections and 43% were outside target range (5-12 mg/L) for other infections using the institution's vancomycin dosing. A one-compartment model best described the observed data with a mean clearance of 0.11 ± 0.03 L/kg/h and volume of distribution (V) of 1.02 ± 0.08 L/kg. Body weight (WT), postmenstrual age (PMA), and serum creatinine (SCr) were significant covariates associated with clearance (p < 0.001) and body WT was a significant covariate associated with V (p = 0.009). Our study's popPK model has similar or better accuracy and precision than other published models. MCS-derived vancomycin doses from the validated model achieved >90% target attainment for a steady state through target range of 10-15 mg/L in the majority of PMA and SCr categories (78%) to treat CoNS sepsis.
A vancomycin dosing guideline derived from a validated popPK model in neonates with CoNS sepsis is recommended to improve target attainment.
由于新生儿的成熟度和器官功能对药代动力学有很大影响，因此为新生儿量身定制万古霉素剂量颇具挑战。群体药代动力学（popPK）模型可用于提高新生儿的靶标达成率。
主要目的是建立和评估新生儿静脉万古霉素的 popPK 模型。其次，比较该 popPK 模型与已发表的 popPK 模型的预测性能。
这是一项回顾性队列研究，纳入了在新生儿重症监护病房接受静脉万古霉素治疗的新生儿。使用非线性混合效应建模方法，对 70%的数据进行了 popPK 模型推导。使用剩余的 30%的数据验证和比较了当前 popPK 模型与 22 个已发表的 popPK 模型的预测性能。通过蒙特卡罗模拟（MCS）来推导治疗凝固酶阴性葡萄球菌（CoNS）引起的新生儿败血症的最佳给药方案。
在 448 例新生儿的 655 个万古霉素疗程中，78%的万古霉素谷浓度不符合中枢神经系统感染的靶范围（10-15mg/L），43%的万古霉素谷浓度不符合其他感染的靶范围（5-12mg/L），而使用的是该机构的万古霉素给药方案。一个单室模型最能描述观察到的数据，平均清除率为 0.11±0.03L/kg/h，分布容积（V）为 1.02±0.08L/kg。体重（WT）、胎龄（PMA）和血清肌酐（SCr）是与清除率显著相关的协变量（p<0.001），而体重是与 V 显著相关的协变量（p=0.009）。与其他已发表的模型相比，我们的研究中的 popPK 模型具有相似或更好的准确性和精密度。验证后的模型中，MCS 推导的万古霉素剂量在大多数 PMA 和 SCr 类别（78%）中达到了 10-15mg/L 的目标范围，从而实现了 CoNS 败血症的稳态时>90%的靶标达成率。
建议为 CoNS 败血症新生儿制定基于验证后的 popPK 模型的万古霉素剂量指南，以提高靶标达成率。
