阿米卡星在老年肾功能不全患者中生理药动学模型的建立与应用 点击下载
| 论文标题： | 阿米卡星在老年肾功能不全患者中生理药动学模型的建立与应用 |
| 英文标题： | |
| 中文摘要： | 目的 建立阿米卡星在老年肾功能不全患者中的生理药动学（PBPK）模型。方法使用PK-SIM®软件进行模型的构建、拟合和模拟。通过查询文献资料，收集阿米卡星的理化性质和体内药动学特性参数，结合软件内置人体模型建立成人PBPK模型并外推至老年PBPK模型。使用临床药动学研究数据对模型进行拟合优化和验证，以拟合优度、相对残差和平均折叠误差为指标评价模型预测性能。使用最终模型模拟老年肾功能不全患者给药后的体内暴露情况，对临床常用给药方案的有效性和安全性进行评估，并给出推荐的给药方案。结果建立的阿米卡星PBPK模型在成人和老年患者中均有较好的预测性能，相对残差绝对值均数为25%；各模拟场合下，峰浓度（cmax）和药时曲线下面积（AUC0－∞）的平均折叠误差均在＞0.5～＜2范围内。模拟结果显示，与健康成人相比，相同给药方案下老年肾功能不全患者的cmax差异较小，因蓄积引起的谷浓度显著升高。与减少剂量相比，延长阿米卡星给药间隔更有助于保证疗效，减少肾毒性的发生。结论成功建立了阿米卡星在老年肾功能不全患者中的PBPK模型，且模型具有良好的预测性能。 |
| 英文摘要： | OBJECTIVE To establish a physiologically-based pharmacokinetic （PBPK） model of amikacin in elderly patients with renal insufficiency. METHODS PK-SIM® software was adopted for model building， optimization and simulation. The physical and chemical properties and pharmacokinetic parameters related to amikacin were collected by literature review. The PBPK model on adults was established and extrapolated to the elderly population based on the built-in human model. Data from clinical PK studies were used to optimize and validate the model. The goodness of fit， relative residual， and mean folding error （MFE） were used to evaluate the performance of forecasting. The final model was employed to simulate the exposure of amikacin in the elderly population with renal insufficiency， and the efficacy and safety of commonly used clinical dosing regimens were evaluated， and the recommended regimens were proposed. RESULTS The established PBPK model of amikacin had good prediction performance in both adult and elderly populations， with the absolute mean of relative residual value of 25%； the MFE of peak concentration （cmax） and area under the plasma concentration curve （AUC0－∞） in all simulation occasions ranged ＞0.5-＜2. The simulation results showed that， compared with healthy adults， no significant clinical difference in cmax was observed in the elderly with renal insufficiency at the same dosing regimen， but the trough concentration increased significantly due to accumulation. Prolonging the administration interval of amikacin rather than reducing the dosage was more helpful to ensure the efficacy and to reduce the occurrence of nephrotoxicity. CONCLUSIONS The PBPK model for amikacin is successfully established in the elderly patient with renal insufficiency， and shows good predictive performance. |
| 期刊： | 2023年第34卷第18期 |
| 作者： | 李乔希；管宴萍；夏晨；吴莉莉；王妍 |
| 英文作者： | LI Qiaoxi，GUAN Yanping，XIA Chen，WU Lili，WANG Yan |
| 关键字： | 阿米卡星；药动学；生理药动学模型；老年人；肾功能不全 |
| KEYWORDS： | amikacin； pharmacokinetics； physiologically-based pharmacokinetic model； the elderly； renal insufficiency |
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