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.
| Original language | English (US) |
|---|---|
| Journal | Journal of Clinical Pharmacology |
| DOIs | |
| State | Published - Jan 1 2019 |
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Keywords
- eclampsia
- exposure-response
- magnesium sulfate
- population modeling
- preeclampsia
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
Cite this
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; Witjes, Han; de Greef, Rik; Lumbiganon, Pisake; Titapant, Vitaya; Kongwattanakul, Kiattisak; Long, Qian; Sangkomkamhang, Ussanee S.; Gülmezoglu, Ahmet M.; Oladapo, Olufemi T.
In: Journal of Clinical Pharmacology, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia
T2 - A Population Pharmacokinetic Exposure-Response Modeling and Simulation Study
AU - Du, Lihong
AU - Wenning, Larissa A.
AU - Carvalho, Brendan
AU - Duley, Lelia
AU - Brookfield, Kathleen
AU - Witjes, Han
AU - de Greef, Rik
AU - Lumbiganon, Pisake
AU - Titapant, Vitaya
AU - Kongwattanakul, Kiattisak
AU - Long, Qian
AU - Sangkomkamhang, Ussanee S.
AU - Gülmezoglu, Ahmet M.
AU - Oladapo, Olufemi T.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - eclampsia
KW - exposure-response
KW - magnesium sulfate
KW - population modeling
KW - preeclampsia
UR - http://www.scopus.com/inward/record.url?scp=85067069116&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067069116&partnerID=8YFLogxK
U2 - 10.1002/jcph.1448
DO - 10.1002/jcph.1448
M3 - Article
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
SN - 0091-2700
ER -