Abstract：
Objectives: To achieve the AUC-guided dosing, we proposed three methods to estimate polymyxin B AUC across 24 h at steady state (AUCSS,24h) using limited concentrations after its first dose.Method: Monte Carlo simulation based on a well-established population PK model was performed to generate the PK profiles of 1000 patients with normal or abnormal renal function. Polymyxin B AUCSS,24h was estimated for each subject using three methods (two-point PK approach, three-point PK approach, and four-point PK approach) based on limited concentration data in its first dose and compared with the actual AUC at steady state calculated using the linear-trapezoidal formula. Sensitivity analysis was performed to examine the influence of each sampling time drifting on the estimated AUCSS,24h.Results: In patients with normal renal function, the mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was -8.73%, 1.37%, and -0.48%, respectively. The corresponding value was -11.15%, 1.99%, and -0.28% in patients with renal impairment, respectively. The largest mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was -12.63%, -6.47%, and -0.54% when the sampling time shifted. Three user-friendly and easy-to-use excel calculators were built based on these methods.Conclusions: Two-point PK approach may be sufficient to guide polymyxin B dosing in patients with normal renal function. For patients with renal insufficiency, three-point PK approach or four-point PK may be a better choice. The Excel calculators designed based on the three methods can be potentially used to optimize the dosing regimen of polymyxin B in the clinic.
摘要：
目标：实现AUC指导给药，我们提出了三种方法来估计稳态下24小时内多粘菌素B的AUC(AUCSS，24h）在首次给药后使用有限的浓度。方法：基于建立良好的人群PK模型进行蒙特卡罗模拟，以生成1000名肾功能正常或异常患者的PK谱。多粘菌素BAUCSS,使用三种方法(两点PK法，三点PK方法，和四点PK方法）基于其第一剂量的有限浓度数据，并与使用线性梯形公式计算的稳态下的实际AUC进行比较。进行了敏感性分析，以检查每个采样时间漂移对估计的AUCSS的影响，24h.结果:肾功能正常的患者,两点PK法的平均偏差，三点PK方法，四点PK方法为-8.73%，1.37%,和-0.48%，分别。相应值为-11.15%，1.99%,和-0.28％的患者肾功能损害，分别。两点PK方法的最大平均偏差，三点PK方法，四点PK方法为-12.63%，-6.47%，当采样时间偏移时，为-0.54%。基于这些方法构建了三个用户友好且易于使用的Excel计算器。结论：两点PK方法可能足以指导肾功能正常患者的多粘菌素B给药。对于肾功能不全的患者，三点PK或四点PK可能是更好的选择。基于这三种方法设计的Excel计算器可用于优化临床多粘菌素B的给药方案。
