Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia
Therapeutics Research Centre, School of Pharmacy, The University of South Australia, Adelaide, Australia.
Antimicrob Agents Chemother. 2017 Oct 24;61(11). doi: 10.1128/AAC.00311-17. Print 2017 Nov.
Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h, and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h High creatinine clearance (CL) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC () of 50%. Only continuous regimens achieved >90% PTA for 100% when CL was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (<85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL or with known/presumed infections from high-MIC bacteria.
已有研究报道，发热性中性粒细胞减少症患者的哌拉西林药代动力学变化可导致药物暴露不足。本研究旨在建立哌拉西林的群体药代动力学模型，并进行给药模拟，以描述血液恶性肿瘤合并发热性中性粒细胞减少症患者的最佳给药方案。浓度-时间数据来自先前的前瞻性观察性药代动力学和干预性治疗药物监测研究。使用 R 语言的 Pmetrics 包进行非参数群体药代动力学分析和蒙特卡罗给药模拟。一个两室模型，清除率（CL）的个体间变异性，充分描述了 37 例患者（21 例男性，年龄 59 ± 12 岁[均值 ± 标准差]，体重 77 ± 16 kg）的数据。参数估计值为 CL 为 18.0 ± 4.8 升/小时，中央室分布容积为 14.3 ± 7.3 升，哌拉西林从中央室向周围室分布的速率常数为 1.40 ± 1.35 小时，哌拉西林从周围室向中央室分布的速率常数为 4.99 ± 7.81 小时。高肌酐清除率（CL）与目标达成率（PTA）降低相关。延长和持续输注方案使未结合哌拉西林浓度保持在 MIC（）以上时，实现了 >90%的高 PTA。只有在 CL 较高时，连续输注方案才能实现 >90%的 PTA 对于 100% 。当考虑 50%和 100%的 FTA 时，延长输注可使累积反应分数（FTA，用于部分目标达成）达到最佳（>85%）。对于经验性和靶向治疗的常规方案，总体而言，哌拉西林药代动力学的变化及其对治疗剂量需求的影响似乎与重症监护患者观察到的相似。指南应针对 CL 较高或已知/假定存在高 MIC 细菌感染的发热性中性粒细胞减少症患者，解决其改变的给药需求。
