Int J Clin Pharmacol Ther. 2022 Sep;60(9):373-383. doi: 10.5414/CP204181.
To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen.
This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥ 60% of the dosing interval (ƒT ≥ 60%).
91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2 ± 0.9 L/h/1.85m, the unbound renal clearance of ceftriaxone divided by the creatinine clearance 0.61 ± 0.24, lean body mass corrected volume of distribution of the central compartment 0.82 ± 0.21 L/kg, and intercompartmental distribution rate constant from central to peripheral compartment 0.18 ± 0.08 h. Dosing simulations predicted ƒT of 88% (95% CI: 69 - 100%) for 2,000 mg ceftriaxone once daily and ƒT of 100% (95% CI: 100 - 100%) both for 1,000 mg twice daily and continuous infusion of 2,000 mg daily.
We developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT ≥ 60% for 1,000 mg twice daily and 2,000 mg once daily or by continuous infusion.
开发一种可靠的两室人群药代动力学（PK）模型，用于估算重症患者游离头孢曲松的浓度，并确定最佳的给药方案。
这是一项针对重症患者接受头孢曲松治疗的前瞻性、单中心、观察性研究。采用经验证的超滤和超高效液相色谱-串联质谱法测定游离血清头孢曲松浓度。采用迭代两阶段贝叶斯拟合程序和蒙特卡罗模拟进行 PK 分析和给药模拟。当游离血清头孢曲松浓度超过最低抑菌浓度（MIC）的 4 倍且超过 60%的给药间隔时间（ƒT ≥ 60%）时，即可达到 PK/药效动力学（PD）目标。
共纳入 91 例患者，共获得 173 例游离头孢曲松浓度。人群 PK 参数估计值为肝清除率 5.2 ± 0.9 L/h/1.85m，头孢曲松的游离肾脏清除率与肌酐清除率之比为 0.61 ± 0.24，中央室的去脂体重校正分布容积为 0.82 ± 0.21 L/kg，以及从中央室到外周室的分布速率常数为 0.18 ± 0.08 h。给药模拟预测，每天给予 2000mg 头孢曲松一次的 ƒT 为 88%（95%可信区间：69-100%），每天给予 1000mg 头孢曲松两次和持续输注 2000mg 头孢曲松的 ƒT 均为 100%（95%可信区间：100-100%）。
我们开发了一种可靠的重症患者游离头孢曲松的人群 PK 模型。给药模拟结果显示，每天给予 1000mg 头孢曲松两次和 2000mg 头孢曲松一次或持续输注均可达到 ƒT ≥ 60%。
