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Abstract：
OBJECTIVE: To establish the population pharmacokinetics (PPK) of magnesium sulfate (MgSO4)in women with preeclampsia (PE), and to determine the key covariates having an effect in magnesium pharmacokinetics in Chinese PE.
METHODS: Pregnant women with PE prescribed MgSO4 were enrolled in this prospective study from April 2021 to April 2023. On the initial day of administration, the patients were administered a loading dose of 5 g in conjunction with 10 g of magnesium sulfate as a maintenance dose. On the second day, only the maintenance dose was administration, and maternal blood samples were taken at 0, 4, 5, and 12 h after the second day\'s 10 g maintenance dose. The software Phoenix was used to estimate PPK parameters of MgSO4, such as clearance (CL) and volume of distribution (V), and to model PPK models with patient demographic, clinical, and laboratory covariates.
RESULTS: A total of 199 blood samples were collected from 51 women with PE and PPK profiles were analyzed. The PPK of MgSO4 is consistent with to a one-compartment model. The base model adequately described the maternal serum magnesium concentrations after magnesium administration. The population parameter estimates were as follows: CL was 2.98 L/h, V was 25.07 L. The model predictions changed significantly with covariates (BMI, creatinine clearance, and furosemide). Furosemide statistically influences V. The creatinine clearance, BMI and furosemide jointly affects CL. Monte Carlo simulation results showed that a loading dose combined with a maintenance dose would need to be administered daily to achieve the therapeutic blood magnesium concentrations. For the non-furosemide group, the optimal dosing regimen was a 5 g loading dose combined with a 10 g maintenance dose of MgSO4. For the furosemide group, the optimal dosing regimen was a 2.5 g loading dose combined with a 10 g maintenance dose of MgSO4.
CONCLUSIONS: The magnesium PPK model was successfully developed and evaluated in Chinese preeclampsia population, and the dose optimization of MgSO4 was completed through Monte Carlo simulation.
METHODS: Pregnant women with PE prescribed MgSO4 were enrolled in this prospective study from April 2021 to April 2023. On the initial day of administration, the patients were administered a loading dose of 5 g in conjunction with 10 g of magnesium sulfate as a maintenance dose. On the second day, only the maintenance dose was administration, and maternal blood samples were taken at 0, 4, 5, and 12 h after the second day\'s 10 g maintenance dose. The software Phoenix was used to estimate PPK parameters of MgSO4, such as clearance (CL) and volume of distribution (V), and to model PPK models with patient demographic, clinical, and laboratory covariates.
RESULTS: A total of 199 blood samples were collected from 51 women with PE and PPK profiles were analyzed. The PPK of MgSO4 is consistent with to a one-compartment model. The base model adequately described the maternal serum magnesium concentrations after magnesium administration. The population parameter estimates were as follows: CL was 2.98 L/h, V was 25.07 L. The model predictions changed significantly with covariates (BMI, creatinine clearance, and furosemide). Furosemide statistically influences V. The creatinine clearance, BMI and furosemide jointly affects CL. Monte Carlo simulation results showed that a loading dose combined with a maintenance dose would need to be administered daily to achieve the therapeutic blood magnesium concentrations. For the non-furosemide group, the optimal dosing regimen was a 5 g loading dose combined with a 10 g maintenance dose of MgSO4. For the furosemide group, the optimal dosing regimen was a 2.5 g loading dose combined with a 10 g maintenance dose of MgSO4.
CONCLUSIONS: The magnesium PPK model was successfully developed and evaluated in Chinese preeclampsia population, and the dose optimization of MgSO4 was completed through Monte Carlo simulation.
摘要：
目的：建立硫酸镁（MgSO4）在先兆子痫（PE）妇女中的群体药代动力学（PPK）。并确定在中国PE中影响镁药代动力学的关键协变量。
方法：在2021年4月至2023年4月的这项前瞻性研究中，招募了使用PE处方MgSO4的孕妇。在管理的第一天，患者的负荷剂量为5g,同时给予10g硫酸镁作为维持剂量.第二天,只有维持剂量是给药，在第2天10g维持剂量后0、4、5和12h采集母体血液样本。Phoenix软件用于估计MgSO4的PPK参数，例如清除率（CL）和分布体积（V），并用患者人口统计来建模PPK模型，临床,和实验室协变量。
结果：共收集了来自51名PE和PPK患者的199份血液样本。MgSO4的PPK与单室模型一致。基础模型充分描述了镁给药后母体血清镁浓度。总体参数估计如下：CL为2.98L/h，V为25.07L。模型预测随协变量(BMI，肌酐清除率,和呋塞米）。呋塞米在统计学上影响V.肌酐清除率，BMI和呋塞米共同影响CL。蒙特卡洛模拟结果表明，需要每天施用负荷剂量与维持剂量相结合以达到治疗性血镁浓度。对于非呋塞米组，最佳给药方案是5g负荷剂量和10g维持剂量的MgSO4.对于呋塞米组，最佳给药方案是2.5g负荷剂量和10g维持剂量的MgSO4.
结论：在中国先兆子痫人群中成功建立并评估了PPK镁模型，并通过蒙特卡罗模拟完成了MgSO4的剂量优化。
方法：在2021年4月至2023年4月的这项前瞻性研究中，招募了使用PE处方MgSO4的孕妇。在管理的第一天，患者的负荷剂量为5g,同时给予10g硫酸镁作为维持剂量.第二天,只有维持剂量是给药，在第2天10g维持剂量后0、4、5和12h采集母体血液样本。Phoenix软件用于估计MgSO4的PPK参数，例如清除率（CL）和分布体积（V），并用患者人口统计来建模PPK模型，临床,和实验室协变量。
结果：共收集了来自51名PE和PPK患者的199份血液样本。MgSO4的PPK与单室模型一致。基础模型充分描述了镁给药后母体血清镁浓度。总体参数估计如下：CL为2.98L/h，V为25.07L。模型预测随协变量(BMI，肌酐清除率,和呋塞米）。呋塞米在统计学上影响V.肌酐清除率，BMI和呋塞米共同影响CL。蒙特卡洛模拟结果表明，需要每天施用负荷剂量与维持剂量相结合以达到治疗性血镁浓度。对于非呋塞米组，最佳给药方案是5g负荷剂量和10g维持剂量的MgSO4.对于呋塞米组，最佳给药方案是2.5g负荷剂量和10g维持剂量的MgSO4.
结论：在中国先兆子痫人群中成功建立并评估了PPK镁模型，并通过蒙特卡罗模拟完成了MgSO4的剂量优化。
