Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure‐Response Modeling and Simulation Study

Abstract

Magnesium sulfate is the anticonvulsant of choice for eclampsia prophylaxis and treatment; however, the recommended dosing regimens are costly and cumbersome and can be administered only by skilled health professionals. The objectives of this study were to develop a robust exposure‐response model for the relationship between serum magnesium exposure and eclampsia using data from large studies of women with preeclampsia who received magnesium sulfate, and to predict eclampsia probabilities for standard and alternative (shorter treatment duration and/or fewer intramuscular injections) regimens. Exposure‐response modeling and simulation were applied to existing data. A total of 10 280 women with preeclampsia who received magnesium sulfate or placebo were evaluated. An existing population pharmacokinetic model was used to estimate individual serum magnesium exposure. Logistic regression was applied to quantify the serum magnesium area under the curve‐eclampsia rate relationship. Our exposure‐response model‐estimated eclampsia rates were comparable to observed rates. Several alternative regimens predicted magnesium peak concentration < 3.5 mmol/L (empiric safety threshold) and eclampsia rate ≤ 0.7% (observed response threshold), including 4 g intravenously plus 10 g intramuscularly followed by either 8 g intramuscularly every 6 hours × 3 doses or 10 g intramuscularly every 8 hours × 2 doses and 10 g intramuscularly every 8 hours × 3 doses. Several alternative magnesium sulfate regimens with comparable model‐predicted efficacy and safety were identified that merit evaluation in confirmatory clinical trials.

Risk factors for sub–therapeutic serum concentrations of magnesium sulfate in severe preeclampsia of Chinese patients

“…Further prospective cohort studies with a larger sample size are necessary to draw any definitive conclusions on these issues. 5The minimum effective treatment concentration of MgSO 4 for prophylaxis and treatment of severe PE has largely been based on clinical and laboratory observations in earlier studies rather than standard exposure-response studies [6,12] .Although some pharmacokinetic studies of MgSO 4 administration in preeclamptic women are reported [29][30][31][32], there has been no rigorous evaluation of therapeutic serum magnesium concentration [11]. In the future, we will conduct a prospective study on whether patients with severe PE can achieve effective treatment concentration with MgSO 4 .…”

Risk Factors for Sub–therapeutic Serum Concentrations of Magnesium Sulfate in Severe Preeclampsia of Chinese Patients

“…Table 1 shows the maternal demographic characteristics, lab test results, the regimens for the administration of MgSO 4 , and serum magnesium levels of the patients in the two groups. The Standard group and Sub-standard group showed no signi cant difference in age (28.00 vs. 31 .007), and higher measurement time (5.00 vs. 1.00, P=0.013) than women in Sub-standard group (P < 0.05). Through univariate analysis, we found that weight, BMI, Ccr, albumin, measurement time, and whether the loading dose was given were statistically signi cant risk factors for sub-therapeutic blood magnesium concentration (P < 0.1, Table 2).…”

“…Further prospective cohort studies with a larger sample size are necessary to draw any de nitive conclusions on these issues. (5) The minimum effective treatment concentration of MgSO 4 for prophylaxis and treatment of severe PE has largely been based on clinical and laboratory observations in earlier studies rather than standard exposure-response studies [6,12] .Although some pharmacokinetic studies of MgSO 4 administration in preeclamptic women are reported [29][30][31][32] , there has been no rigorous evaluation of therapeutic serum magnesium concentration [11] . In the future, we will conduct a prospective study on whether patients with severe PE can achieve effective treatment concentration with MgSO 4 .…”

Risk Factors for Sub–therapeutic Serum Concentrations of Magnesium Sulfate in Severe Preeclampsia of Chinese Patients

“…Further prospective cohort studies with a larger sample size are necessary to draw any de nitive conclusions on these issues. (5) The minimum effective treatment concentration of MgSO 4 for prophylaxis and treatment of severe PE has largely been based on clinical and laboratory observations in earlier studies rather than standard exposure-response studies [6,17] Although some pharmacokinetic studies of MgSO 4 administration in preeclamptic women are reported [25][26][27][28][29] , there has been no rigorous evaluation of therapeutic serum magnesium concentration [14] .…”