硫酸镁防治子痫前期群体药物动力学模型的构建与临床应用

Construction and clinical application of a population pharmacokinetic model for magnesium sulfate in the prevention and treatment of pre-eclampsia

Key words:  硫酸镁  子痫前期  群体药动学  血肌酐  非线性混合效应模型

Key words:  magnesium sulfate  pre-eclampsia  population pharmacokinetics  serum creatinine  nonlinear mixed effects model

Abstract:

目的 建立防治子痫前期的硫酸镁群体药动学模型并用于临床实践。 方法 回顾性查询2018年7月—2023年10月同济大学附属妇产科医院ICU病区用硫酸镁防治子痫前期患者的病历，收集年龄、身高、体质量、血肌酐、肌酐清除率、体质量指数(body mass index, BMI)、体表面积、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、总胆红素、直接胆红素、白蛋白水平等以及同期用药(包括呋塞米、胰岛素、β受体阻断剂、钙离子拮抗剂、人血白蛋白和纤维蛋白原)等资料，用非线性混合效应模型（NONMEM）软件估算硫酸镁药动学模型参数和协变量，使用拟合优度图、自举法进行最终模型评价，使用最终模型模拟估算不同协变量人群的硫酸镁用量。 结果 共收集到101例患者的429个镁浓度，用一级消除二室模型拟合，镁浓度基线水平0.772 mmol/L，群体典型值CL、V1、Q和V2分别为3.29 L/h、21.5 L、4.17 L/h和23.3 L，血清肌酐是影响患者硫酸镁CL的显著协变量。目标镁浓度2 mmol/L时，血清肌酐值＜50、50~90和＞90 μmol/L的硫酸镁维持用量分别为2、1.5和1 g/h。 结论 该群体药动学模型有助于临床精准使用硫酸镁防治子痫前期。

Abstract:

Objective To establish a population pharmacokinetic model of magnesium sulfate for the prevention and treatment of pre-eclampsia and apply it in clinical practice. Methods The medical records of patients who receiving magnesium sulfate treatment for pre-eclampsia in the ICU ward of Obstetrics and Gynecology Hospital of Tongji University from July 2018 to October 2023 were retrospectively reviewed. The data of the patients were collected, such as age, height, weight, serum creatinine, creatinine clearance, body mass index(BMI), body surface area, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, albumin levels, and concurrent use of medicine, including furosemide, insulin, beta-blockers, calcium channel blockers, human albumin, and fibrinogen. The nonlinear mixed effects model(NONMEM) software was used to estimate the pharmacokinetic model parameters and covariates for magnesium sulfate. Goodness-of-fit plots and Bootstrap were used for model evaluation. The final model was used to simulate and estimate magnesium sulfate dosage for different covariate populations. Results A total of 101 patients and 429 magnesium ion concentrations were included in the analysis. A first-order elimination two-compartment model was fitted, with a baseline magnesium concentration of 0.772 mmol/L. The typical values for CL, V1, Q, and V2 was 3.29 L/h, 21.5 L, 4.17 L/h, and 23.3 L, respectively. Serum creatinine was found to be a significant covariate that affected the clearance of magnesium sulfate in patients. Maintenance doses of magnesium sulfate to achieve a target concentration of 2 mmol/L was 2, 1.5, and 1 g/h for serum creatinine values <50, 50-90, and >90 μmol/L, respectively. Conclusion This population pharmacokinetic model can facilitate the precise use of magnesium sulfate for the prevention and treatment of pre-eclampsia in clinical practice.