table1_Population Pharmacokinetics and Model-Based Dosing Optimization of Teicoplanin in Pediatric Patients.docx

Objectives: The pharmacokinetics (PK) of teicoplanin differs in children compared with adults. Our aim was to determine the PK of teicoplanin in an Asian pediatric population and to optimize dosage regimens.
Methods: This was a retrospective PK study and all the data were collected from hospitalized children. We developed a population PK model using sparse data, and Monte Carlo simulation was used to assess the ability of standard teicoplanin regimen and other different dosage regimens. The optimal dosing regimens were defined as achieving the target trough concentration (Cmin) of 10 mg/L and pharmacokinetic/pharmacodynamic (PK/PD, [AUC24/MIC]) of 125 for moderate infection. For severe infection, the optimal dosing regimens were defined as achieving the target 15 mg/L and AUC24/MIC of 345.
Results: 159 children were included and 1.5 samples/children on average were provided. Estimated clearance of teicoplanin was 0.694 L/h (0.784/L/h/70 kg) and volume of distribution was 1.39 L. Teicoplanin standard loading dose was adequate for moderate infection, while 13 mg/kg was needed for severer infection. With standard maintenance doses, both patients with moderate and severe infection failed to achieve the target Cmin. 12 and 16 mg/kg/day were required to achieve a Cmin ≥ 10 and 15 mg/L, respectively. However, standard maintenance dose was adequate to achieve AUC24/MIC ≥ 125 for moderate infection, and 12 mg/kg/day was needed to achieve AUC24/MIC ≥ 345 for severe infection. Lower weight and serum creatinine were associated with higher dose.
Conclusion: Optimal doses based on the target Cmin were higher than that based on the PK/PD target. To achieve the Cmin and PK/PD targets simultaneously, a standard loading dose was adequate for moderate infection based on simulation, while dosing higher than standard doses were required in other situation. Further clinical studies with rich sampling from children is required to confirm our findings.

研究目的：替考拉宁（teicoplanin）的药代动力学（pharmacokinetics, PK）在儿童与成人中存在差异。本研究旨在明确亚洲儿科人群中替考拉宁的药代动力学特征，并优化其给药方案。
研究方法：本研究为回顾性药代动力学研究，所有数据均来自住院儿童。研究采用稀疏数据构建群体药代动力学模型，并通过蒙特卡洛模拟（Monte Carlo simulation）评估标准替考拉宁给药方案及其他不同给药方案的效果。本研究将中度感染的目标谷浓度（Cmin）设定为10 mg/L、药代动力学/药效动力学（PK/PD，[AUC₂₄/MIC]）目标值设定为125，以此定义最优给药方案；对于重度感染，则将目标谷浓度设定为15 mg/L、AUC₂₄/MIC目标值设定为345。
研究结果：本研究共纳入159名儿童，平均每名儿童提供1.5份样本。替考拉宁的表观清除率为0.694 L/h（每70kg体重的清除率为0.784 L/h），分布容积为1.39 L。标准替考拉宁负荷剂量可满足中度感染的需求，但重度感染则需采用13 mg/kg的负荷剂量。采用标准维持剂量时，中度与重度感染患者均无法达到目标谷浓度；分别需采用12 mg/kg/日及16 mg/kg/日的给药方案，方可使谷浓度达到≥10 mg/L及≥15 mg/L。不过，对于中度感染，标准维持剂量即可使AUC₂₄/MIC达到≥125；而重度感染则需采用12 mg/kg/日的给药方案，方可使AUC₂₄/MIC达到≥345。患者体重更低、血清肌酐水平更高，与所需给药剂量更高显著相关。
结论：基于谷浓度目标制定的最优给药剂量，高于基于PK/PD目标的给药剂量。模拟结果显示，若需同时达到谷浓度与PK/PD目标，对于中度感染，标准负荷剂量即可满足需求；而其他情况则需采用高于标准剂量的给药方案。未来需开展针对儿童的多采样临床研究，以验证本研究结果。