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

Du, Lihong; Wenning, Larissa A.; Carvalho, Brendan; Duley, Lelia; Brookfield, Kathleen F.; Witjes, Han; de Greef, Rik; Lumbiganon, Pisake; Titapant, Vitaya; Kongwattanakul, Kiattisak; Long, Qian; Sangkomkamhang, Ussanee S.; Gulmezoglu, Ahmet M.; Oladapo, Olufemi T.

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.

Citation

Du, L., Wenning, L. A., Carvalho, B., Duley, L., Brookfield, K. F., Witjes, H., de Greef, R., Lumbiganon, P., Titapant, V., Kongwattanakul, K., Long, Q., Sangkomkamhang, U. S., Gulmezoglu, A. M., & Oladapo, O. T. (2019). Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure-Response Modeling and Simulation Study. Journal of Clinical Pharmacology, 59(11), 1519-1526. https://doi.org/10.1002/jcph.1448

• Journal Article Type: Article
• Acceptance Date: May 9, 2019
• Online Publication Date: Jun 3, 2019
• Publication Date: Jun 3, 2019
• Deposit Date: Jun 25, 2019
• Publicly Available Date: Jun 27, 2019
• Journal: The Journal of Clinical Pharmacology
• Print ISSN: 0091-2700
• Electronic ISSN: 1552-4604
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 11
• Pages: 1519-1526
• DOI: https://doi.org/10.1002/jcph.1448
• Keywords: Eclampsia, Exposure-response, Magnesium sulfate, Population modeling, Preeclampsia
• Public URL: https://nottingham-repository.worktribe.com/output/2226413
• Publisher URL: https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.1448
• Additional Information: This is the peer reviewed version of the following article: Du, L. , Wenning, L. A., Carvalho, B. , Duley, L. , Brookfield, K. F., Witjes, H. , Greef, R. , Lumbiganon, P. , Titapant, V. , Kongwattanakul, K. , Long, Q. , Sangkomkamhang, U. S., Gülmezoglu, A. M. and Oladapo, O. T. (2019), Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure‐Response Modeling and Simulation Study. The Journal of Clinical Pharmacology. doi:10.1002/jcph.1448, which has been published in final form at https://doi.org/10.1002/jcph.1448; . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
• Contract Date: Jun 27, 2019