Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Cancer Rep (Hoboken). 2022 Oct;5(10):e1585. doi: 10.1002/cnr2.1585. Epub 2021 Nov 18.
Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.
This study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen.
This prospective PK study included children with cancer, aged 1-17 years, who were treated with piperacillin-tazobactam for suspected or verified infection. A piperacillin-tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high-performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC.
We included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1-54.0). A three-compartment model adequately described the concentration-time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses.
Unlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.
患有发热性中性粒细胞减少症的儿童通常表现出药代动力学（PK）参数的改变，导致β-内酰胺浓度降低。
本研究评估了哌拉西林他唑巴坦连续输注的 PK 及目标达标概率（PTA），以优化给药方案。
本前瞻性 PK 研究纳入了年龄在 1-17 岁、因疑似或确诊感染而接受哌拉西林他唑巴坦治疗的癌症患儿。先给予哌拉西林他唑巴坦负荷剂量（100mg/kg），然后持续输注（300mg/kg/天）。采用高效液相色谱法测定哌拉西林游离分数，并采用群体 PK 模型描述 PK。PK 数据用于更新和扩展基于间歇性给药数据建立的先前 PK 模型。通过蒙特卡罗模拟评估 100%时间高于最低抑菌浓度（100%fT> MIC）和 50%fT> 4xMIC 的目标达标概率（PTA）。
我们纳入了 38 名儿童 68 次发热发作的数据，中位数（IQR）年龄为 6.5 岁，体重为 27.4kg（15.1-54.0）。三房室模型能很好地描述浓度-时间数据。清除率和哌拉西林稳态时的浓度中位数（95%置信区间）估计值分别为 14.2L/h/70kg（13.0；15.3）和 47.6mg/L（17.2；129.5）。体重或去脂体重与 PK 参数显著相关，体重被纳入最终 PK 模型。基于哌拉西林暴露情况，连续输注是达到铜绿假单胞菌折点（16mg/L）100%fT> MIC 的唯一给药方案，每日 300mg/kg 剂量可达到最佳 PTA。任何推荐剂量的给药方案都无法达到严格的 50%fT> 4xMIC（64mg/L）目标。
与传统的哌拉西林间歇性给药和延长输注方案不同，连续输注可使发热性中性粒细胞减少症患儿达到 100%fT> MIC 的目标。
