Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia

Abstract

Magnesium sulfate is the standard therapy for prevention and treatment of eclampsia. Two standard dosing regimens require either continuous intravenous infusion or frequent, large‐volume intramuscular injections, which may preclude patients from receiving optimal care. This project sought to identify alternative, potentially more convenient, but similarly effective dosing regimens that could be used in restrictive clinical settings. A 2‐compartment population pharmacokinetic (PK) model was developed to characterize serial PK data from 92 pregnant women with preeclampsia who received magnesium sulfate. Body weight and serum creatinine concentration had a significant impact on magnesium PK. The final PK model was used to simulate magnesium concentration profiles for the 2 standard regimens and several simplified alternative dosing regimens. The simulations suggest that intravenous regimens with loading doses of 8 g over 60 minutes followed by 2 g/h for 10 hours and 12 g over 120 minutes followed by 2 g/h for 8 hours (same total dose as the standard intravenous regimen but shorter treatment duration) would result in magnesium concentrations below the toxic range. For the intramuscular regimens, higher maintenance doses given less frequently (4 g intravenously + 10‐g intramuscular loading doses with maintenance doses of 8 g every 6 hours or 10 g every 8 hours for 24 hours) or removal of the intravenous loading dose (eg, 10 g intramusculary every 8 hours for 24 hours) may be reasonable alternatives. In addition, individualized dose adjustments based on body weight and serum creatinine were proposed for the standard regimens.

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

“…Model estimated clearance was 3.72 L/h, and distribution volume was 32.4 L/85 kg. The final model structure and simulated magnesium profiles for standard and alternative intravenous and intramuscular regimens are provided in Supplemental Table and Supplemental Figures and (additional details can be found in the previous publication) . The second part (presented in the current article) consisted of exposure‐response (E‐R) modeling using pooled clinical outcome data from the Thai study and the Magpie Trial to predict magnesium exposure and the probability of eclampsia for various MgSO 4 dosing regimens.…”

“…Supplemental presents a summary of the characteristics of the 3 studies used to develop the population PK model and the E‐R model (current analysis).…”

“…No serum magnesium samples were collected in the Magpie Trial, and only sparse postdose samples were collected in the Thai study. Therefore, serum magnesium pharmacokinetic exposure, expressed as area under the curve (AUC) for change from baseline in serum magnesium concentration, was estimated using the pharmacokinetic model . Subsequently, the relationship between the projected AUC and the observed eclampsia outcome was quantified using a logistic regression approach.…”

“…Using the established pharmacokinetic model, individual AUCs were predicted based on actual dose amount, route of administration (intravenous or intramuscular) and covariates of body weight and serum creatinine. Individual AUC values for the change from baseline serum magnesium concentration were calculated using the clearance (CL) function derived from the population pharmacokinetic model according to the following equations: …”

“…Therefore, serum magnesium pharmacokinetic exposure, expressed as area under the curve (AUC) for change from baseline in serum magnesium concentration, was estimated using the pharmacokinetic model. 4 Subsequently, the relationship between the projected AUC and the observed eclampsia outcome was quantified using a logistic regression approach. Using the developed E-R model, the probability of eclampsia occurrence was predicted for different types of "typical" women who received the standard Zuspan and Pritchard regimens and a series of simplified alternative intravenous and intramuscular dosing regimens that were considered more practical and/or convenient compared with the standard regimens, by virtue of fewer injections, shorter treatment duration, or lower doses.…”