DataSheet2_Population pharmacokinetics and individualized dosing of tigecycline for critically ill patients: a prospective study with intensive sampling.PDF

Background: Due to the heterogeneity of critically ill patients, the pharmacokinetics of tigecycline are unclear, and the optimal dosing strategy is controversial.
Methods: A single-center prospective clinical study that included critically ill patients who received tigecycline was performed. Blood samples were intensively sampled (eight samples each), and plasma drug concentrations were determined. A population pharmacokinetic (PPK) model was developed and evaluated by goodness-of-fit plots, bootstrap analysis and visual predictive checks. Monte Carlo simulation was conducted to optimize the dosage regimen.
Results: Overall, 751 observations from 98 patients were included. The final PPK model was a two-compartment model incorporating covariates of creatinine clearance on clearance (CL), body weight on both central and peripheral volumes of distribution (V1 and V2), γ-glutamyl transferase and total bilirubin on intercompartment clearance (Q), and albumin on V2. The typical values of CL, Q, V1 and V2 were 3.09 L/h, 39.7 L/h, 32.1 L and 113 L, respectively. A dosage regimen of 50 mg/12 h was suitable for complicated intra-abdominal infections, but 100 mg/12 h was needed for community-acquired pneumonia, skin and skin structure infections and infections caused by less-susceptive bacteria.
Conclusion: The Tigecycline PPK model was successfully developed and validated. Individualized dosing of tigecycline could be beneficial for critically ill patients.

背景：由于重症患者存在异质性，替加环素（tigecycline）的药代动力学特征尚不明确，其最优给药策略亦存在争议。
方法：本研究为单中心前瞻性临床研究，纳入接受替加环素治疗的重症患者。对所有受试者采集密集血样（每人8份），并测定血浆药物浓度。通过拟合优度图、Bootstrap自举分析及可视化预测检验，构建并验证了群体药代动力学（PPK）模型。采用蒙特卡洛（Monte Carlo）模拟对给药方案进行优化。
结果：本研究共纳入98例患者的751条观测数据。最终构建的PPK模型为二室模型，纳入的协变量包括：肌酐清除率对清除率（CL）的影响、体质量对中央及外周分布容积（V1、V2）的影响、γ-谷氨酰转移酶与总胆红素对室间清除率（Q）的影响，以及白蛋白对V2的影响。CL、Q、V1及V2的典型值分别为3.09 L/h、39.7 L/h、32.1 L及113 L。50 mg/12 h的给药方案适用于复杂性腹腔内感染，但社区获得性肺炎、皮肤及皮肤软组织感染，以及低敏感性细菌所致感染需采用100 mg/12 h的给药方案。
结论：本研究成功构建并验证了替加环素PPK模型，为重症患者实施替加环素个体化给药方案可带来临床获益。