@article{ecaaefe2e5c44d2cac388bdff3bc1eaf,
title = "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.",
keywords = "eclampsia, exposure-response, magnesium sulfate, population modeling, preeclampsia",
author = "Lihong Du and Wenning, {Larissa A.} and Brendan Carvalho and Lelia Duley and Brookfield, {Kathleen F.} and Han Witjes and {de Greef}, Rik and Pisake Lumbiganon and Vitaya Titapant and Kiattisak Kongwattanakul and Qian Long and Sangkomkamhang, {Ussanee S.} and G{\"u}lmezoglu, {Ahmet M.} and Oladapo, {Olufemi T.}",
note = "Funding Information: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored program executed by the World Health Organization (WHO). We acknowledge Priya Agrawal (Merck & Co., Inc., Nottingham, East Midlands, UK) and Jeffrey Jacobs (MSD for Mothers). The authors thank all the study investigators, including the Magpie Trial Collaborative Group, who generated the data used for these studies, and their staff at the clinical study sites for their valuable contributions. In addition, the authors thank Stanford University (Stanford, California), Oxford University (United Kingdom), and Siriraj Hospital and Khon Kaen Hospitals, Thailand, for providing data for this study. Medical Writing was coordinated and supported by Certara Strategic Consulting and Medical Writing Innovations, LLC. The article represents the views of the named authors only. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored program executed by the World Health Organization (WHO). The authors are unable to share the data supporting the results of this study. Publisher Copyright: {\textcopyright} 2019 Meck Sharp & Dohme Corp. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology",
year = "2019",
month = nov,
day = "1",
doi = "10.1002/jcph.1448",
language = "English (US)",
volume = "59",
pages = "1519--1526",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "11",
}