Barreto Erin F, Chang Jack, Rule Andrew D, Cole Kristin C, Fogelson Lindsay, Paul Johar, Jannetto Paul J, Athreya Arjun P, Scheetz Marc H
Department of Pharmacy, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905.
Clinical Pharmacology Sciences, Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA 94404.
Int J Antimicrob Agents. 2025 Aug 1:107586. doi: 10.1016/j.ijantimicag.2025.107586.
As a renally-eliminated beta-lactam antibiotic, estimated glomerular filtration rate (eGFR) is a central component of piperacillin/tazobactam pharmacokinetics. This study aimed to determine the optimal eGFR equation for inclusion in population pharmacokinetic models for piperacillin and tazobactam among critically ill adults.
The study included critically ill adults treated with piperacillin/tazobactam at a single academic medical center between 2018 and 2022. Excluded individuals had acute kidney injury, received kidney replacement therapy, or had extracorporeal membrane oxygenation at piperacillin/tazobactam initiation. Non-linear mixed effects population pharmacokinetic models using eGFR equations with creatinine, cystatin C, or both were developed and compared.
Using 377 samples from 120 critically ill patients, we found that a two-compartment model with first-order elimination best fit the piperacillin data and a one-compartment model with first-order elimination best fit the tazobactam data. For piperacillin, the final population mean parameters (standard error) were 8.36 (0.55) L/h for CL and 12.96 (1.17) L for V1. The values for Q and V2 were fixed at 0.98 L/h and 18 L, respectively, due to low interindividual variation in these parameters. For tazobactam, the final population mean parameters were 8.12 (0.52) L/h for CL and 16.87 (1.44) L for V. Both final models identified eGFR expressed in mL/min as the eGFR equation that best predicted drug clearance as a covariate.
An eGFR equation that includes cystatin C improves the predictive performance of pharmacokinetic models for piperacillin/tazobactam in critically ill adults.
作为一种经肾脏排泄的β-内酰胺类抗生素，估计肾小球滤过率（eGFR）是哌拉西林/他唑巴坦药代动力学的核心组成部分。本研究旨在确定用于危重症成年患者哌拉西林和他唑巴坦群体药代动力学模型的最佳eGFR方程。
本研究纳入了2018年至2022年间在一家学术医疗中心接受哌拉西林/他唑巴坦治疗的危重症成年患者。排除在开始使用哌拉西林/他唑巴坦时患有急性肾损伤、接受肾脏替代治疗或进行体外膜肺氧合的个体。使用含肌酐、胱抑素C或两者的eGFR方程开发并比较了非线性混合效应群体药代动力学模型。
利用120例危重症患者的377份样本，我们发现具有一级消除的二室模型最适合哌拉西林数据，具有一级消除的一室模型最适合他唑巴坦数据。对于哌拉西林，最终群体平均参数（标准误差）为CL：8.36（0.55）L/h，V1：12.96（1.17）L。由于这些参数的个体间差异较小，Q和V2的值分别固定为0.98 L/h和18 L。对于他唑巴坦，最终群体平均参数为CL：8.12（0.52）L/h，V：16.87（1.44）L。两个最终模型均将以mL/min表示的eGFR方程确定为作为协变量最佳预测药物清除率的eGFR方程。
包含胱抑素C的eGFR方程可提高危重症成年患者哌拉西林/他唑巴坦药代动力学模型的预测性能。
