The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus

Abhishek G. Sathe; Jordan J. Elm; James C. Cloyd; James M. Chamberlain; Robert Silbergleit; Jaideep Kapur; Hannah R. Cock; Nathan B. Fountain; Shlomo Shinnar; Daniel H. Lowenstein; Robin A. Conwit; Thomas P. Bleck; Lisa D. Coles

doi:10.1111/epi.16534

The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus

Abhishek G. Sathe, Jordan J. Elm, James C. Cloyd, James M. Chamberlain, Robert Silbergleit, Jaideep Kapur, Hannah R. Cock, Nathan B. Fountain, Shlomo Shinnar, Daniel H. Lowenstein, Robin A. Conwit, Thomas P. Bleck, Lisa D. Coles

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

Original language	English (US)
Pages (from-to)	e66-e70
Journal	Epilepsia
Volume	61
Issue number	6
DOIs	https://doi.org/10.1111/epi.16534
State	Published - Jun 1 2020

Bibliographical note

Funding Information:
H.R.C. received consulting fees from BIAL Pharma UK and Sage Therapeutics; her institution has received funds for her work on other trials from UCB Pharma, Eisai Europe, Novartis, and GW Pharma. N.B.F. reports research grants awarded to the University of Virginia with N.B.F. as principal investigator from the Epilepsy Foundation, InSightech, UCB, SK Life Sciences, GW Pharmaceuticals, Neurelis, Takeda, Medtronic, and Cerebral Therapeutics. D.H.L. has served on the scientific advisory board of Bloom Science. J.C.C. received consulting fees from Neurelis Pharmaceuticals and reports funding awarded to University of Minnesota from Neurelis, holds a patent US9629797B2 on intravenous carbamazepine and intellectual property on intravenous topiramate, licensed to Ligand. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Funding Information:
Research reported in this article was supported by the National Institutes of Health, National Institutes of Neurological Disorders and Stroke under awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653. Clinical trials.gov identifier is NCT01960075. A.G.S. was supported in part by the OLSTEINS Graduate Fellowship from the College of Pharmacy, University of Minnesota. We would like to acknowledge the ESETT Data and Safety Monitoring Board. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, or the United States Government.

Funding Information:
Research reported in this article was supported by the National Institutes of Health, National Institutes of Neurological Disorders and Stroke under awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653. Clinical trials.gov identifier is NCT01960075. A.G.S. was supported in part by the OLSTEINS Graduate Fellowship from the College of Pharmacy, University of Minnesota. We would like to acknowledge the ESETT Data and Safety Monitoring Board. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, or the United States Government.

Publisher Copyright:
© 2020 International League Against Epilepsy

Keywords

ESETT
antiseizure medications
dose-response
seizure cessation
weight-based dosing

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10.1111/epi.16534

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Sathe, A. G., Elm, J. J., Cloyd, J. C., Chamberlain, J. M., Silbergleit, R., Kapur, J., Cock, H. R., Fountain, N. B., Shinnar, S., Lowenstein, D. H., Conwit, R. A., Bleck, T. P., & Coles, L. D. (2020). The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus. Epilepsia, 61(6), e66-e70. https://doi.org/10.1111/epi.16534

Sathe, AG, Elm, JJ, Cloyd, JC, Chamberlain, JM, Silbergleit, R, Kapur, J, Cock, HR, Fountain, NB, Shinnar, S, Lowenstein, DH, Conwit, RA, Bleck, TP & Coles, LD 2020, 'The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus', Epilepsia, vol. 61, no. 6, pp. e66-e70. https://doi.org/10.1111/epi.16534

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title = "The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus",

abstract = "The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.",

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note = "Funding Information: H.R.C. received consulting fees from BIAL Pharma UK and Sage Therapeutics; her institution has received funds for her work on other trials from UCB Pharma, Eisai Europe, Novartis, and GW Pharma. N.B.F. reports research grants awarded to the University of Virginia with N.B.F. as principal investigator from the Epilepsy Foundation, InSightech, UCB, SK Life Sciences, GW Pharmaceuticals, Neurelis, Takeda, Medtronic, and Cerebral Therapeutics. D.H.L. has served on the scientific advisory board of Bloom Science. J.C.C. received consulting fees from Neurelis Pharmaceuticals and reports funding awarded to University of Minnesota from Neurelis, holds a patent US9629797B2 on intravenous carbamazepine and intellectual property on intravenous topiramate, licensed to Ligand. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Funding Information: Research reported in this article was supported by the National Institutes of Health, National Institutes of Neurological Disorders and Stroke under awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653. Clinical trials.gov identifier is NCT01960075. A.G.S. was supported in part by the OLSTEINS Graduate Fellowship from the College of Pharmacy, University of Minnesota. We would like to acknowledge the ESETT Data and Safety Monitoring Board. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, or the United States Government. Funding Information: Research reported in this article was supported by the National Institutes of Health, National Institutes of Neurological Disorders and Stroke under awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653. Clinical trials.gov identifier is NCT01960075. A.G.S. was supported in part by the OLSTEINS Graduate Fellowship from the College of Pharmacy, University of Minnesota. We would like to acknowledge the ESETT Data and Safety Monitoring Board. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, or the United States Government. Publisher Copyright: {\textcopyright} 2020 International League Against Epilepsy",

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AU - Cloyd, James C.

AU - Chamberlain, James M.

AU - Silbergleit, Robert

AU - Kapur, Jaideep

AU - Cock, Hannah R.

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N2 - The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

AB - The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

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The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus

Abstract

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