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Epilepsia. Author manuscript; available in PMC 2022 July 14.
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Epilepsia. 2020 June ; 61(6): e66–e70. 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. Sathe1, Jordan J. Elm2, James C. Cloyd1, James M. Chamberlain3, Robert
Silbergleit4, Jaideep Kapur5,6, Hannah R. Cock7, Nathan B. Fountain8, Shlomo Shinnar9,
Daniel H. Lowenstein10, Robin A. Conwit11, Thomas P. Bleck12, Lisa D. Coles1
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1Department of Experimental and Clinical Pharmacology and Center for Orphan Drug Research,
College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
2Department of Public Health Science, Medical University of South Carolina, Charleston, South
Carolina
3Divisionof Emergency Medicine, Department of Pediatrics and Emergency Medicine, School
of Medicine and Health Sciences, Children’s National Hospital, George Washington University,
Washington, District of Columbia
4Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan
5Department of Neurology, Brain Institute, University of Virginia, Charlottesville, Virginia
6Department of Neuroscience, Brain Institute, University of Virginia, Charlottesville, Virginia
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7Clinical
Neurosciences Academic Group, Institute of Molecular and Clinical Sciences, St
George’s University of London, London, UK
8Department of Neurology, Comprehensive Epilepsy Program, University of Virginia,
Charlottesville, Virginia
9Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
10Department of Neurology, University of California, San Francisco, San Francisco, California
11National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda,
Maryland
12Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Correspondence: Abhishek G. Sathe, Center for Orphan Drug Research/Experimental and Clinical Pharmacology, College of
Pharmacy, University of Minnesota, Rm 4-226, McGuire Translational Research Facility, 2001 6th St SE, Minneapolis, MN 55455.
sathe134@umn.edu.
CONFLICT OF INTEREST
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.
 Sathe et al. Page 2

Abstract
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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.
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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.

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

1| INTRODUCTION
The Established Status Epilepticus Treatment Trial (ESETT), which completed enrollment
in January 2019, was a multicenter, randomized, double-blind study to determine the best or
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worst second-line treatment among fosphenytoin (FOS), levetiracetam (LEV), and valproic
acid (VPA) in patients with benzodiazepine-refractory status epilepticus (SE).1 The primary
outcome of the study was cessation of SE at 60 minutes after the start of study drug infusion
without use of additional antiseizure medication, as determined by absence of clinically
apparent seizures and improved consciousness. Subjects aged ≥2 years who failed first-line
treatment with benzodiazepines and continued to have seizures were included in this study.

To maintain the blind, the three drugs, FOS, LEV, and VPA, had to be administered at
the same volume and infusion rate even though the drugs had different mg/kg doses.2 The
FOS product label recommends a maximum dose of FOS (prodrug of phenytoin) of 20 mg
phenytoin equivalents (PE)/kg and that the rate of intravenous administration should not
exceed 150 mg PE per minute due to cardiovascular risks associated with rapid injection.3
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Given that the ESETT protocol fixed the infusion time at 10 minutes, dosing was capped at
1500 mg PE. As a result, all patients weighing ≥75 kg received the same capped dose of
FOS (20 mg/kg, maximum = 1500 mg PE). Similarly, weight-based dosing was also capped
at 75 kg for LEV (60 mg/kg, maximum = 4500 mg) and VPA (40 mg/kg, maximum = 3000
mg).

Patients weighing >75 kg received a lower mg/kg dose; thus, lower drug exposure would
be expected given the pharmacokinetic properties of these drugs. Therefore, we performed

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a secondary analysis to assess whether the odds of treatment success were lower in patients
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weighing >75 kg as compared to those weighing ≤75 kg. Because a primary outcome failure
could be a result of one or more of the following: (1) need for an additional antiseizure
medication before 60 minutes, (2) clinically apparent seizures at 60 minutes, and (3) lack of
improvement in consciousness and response at 60 minutes, we also evaluated the association
of weight and other predictors with clinical seizure cessation alone at 60 minutes.

2| MATERIALS AND METHODS

ESETT was approved by institutional review boards for all participating institutions.1 Of
the 478 patients enrolled in ESETT, 48.2% of adults and 0.9% of children weighed >75 kg.
Because of the low number of children receiving a fixed dose and the possibility of differing
response rates within children and adults, the analyses were limited to those ≥18 years old (n
= 249). Two patients were excluded because the study drug volume administered could not
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be determined. Among the 247 enrollments, 12 patients were enrolled more than once but
only their first enrollments were used. Among the 235 unique adult patients, 132 (56.2%)
failed the ESETT primary outcome. Of the 132 failures, 87 (65.9%) failed because they
needed an additional antiseizure medication prior to 60 minutes, 10 (7.6%) failed due to
clinically apparent seizures at 60 minutes, and 35 (26.5%) failed because they did not show
an improvement in responsiveness at 60 minutes despite clinical seizure cessation.

2.1 | ESETT primary outcome as the dependent variable

The ESETT primary outcome was expressed as binary (0 = treatment failure, 1 = treatment
success) and used as the dependent variable for the following logistic regression models.

2.1.1 | Association of weight with primary outcome using univariate and

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multivariate analyses—Two logistic regression models were used to test the association
of weight, as a binary predictor, with primary outcome using weight cutoffs of 75 and
90 kg, respectively. A 90-kg cutoff was chosen to examine the association for higher
weight individuals more rigorously. A logistic regression model also tested association of
interactions of weight, sex, and treatment with the primary outcome. The model included
treatment group (FOS, LEV, or VPA), sex (male or female), and weight as binary (≤ or
>75 kg), with all the interaction terms (weight × treatment group × sex) as predictors of the
primary outcome.

2.1.2 | Association of weight-normalized dose and sex with primary outcome

—Separate logistic regression models were built for FOS, LEV, and VPA to test the
association of weight-normalized dose in mg/kg as a continuous variable, sex (male or
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female), and the interaction of dose and sex with the ESETT primary outcome.

2.1.3 | Association of weight, sex, and treatment with clinical seizure

cessation without additional antiseizure medication—A logistic regression model
was used to test the association of weight and other predictors with clinical seizure cessation
without additional antiseizure medication. Adult ESETT patients whose seizures were
terminated but failed the primary outcome due to lack of improved responsiveness at 60
minutes (n = 35) were treated as successes. Clinical seizure cessation, as binary (1 = success,

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0 = failure), was used as the dependent variable for this analysis. A logistic model with
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weight, as a binary (≤ or >75 kg), sex (male or female), and treatment group (FOS, LEV, or
VPA) with all interactions (weight × treatment group × sex) as predictors was used to test
their association with clinical seizure cessation.

Significance was determined as an alpha level < .05. All the analyses were conducted using
R (v3.6.1), RStudio (v1.2.5001), and SAS (v9.4).

3| RESULTS
3.1 | Distribution of weights
ESETT patients ≥18 years old weighed from 36 to 157 kg and weights were approximately
normally distributed, with a mean of 76.7 kg and standard deviation of 18.9 kg (Figure 1).
Of the 235 patients, 113 (48.1%) weighed >75 kg and received the maximum doses. The
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overall success rate for the primary outcome was 45.1% in those ≤75 kg versus 42.5% in
those >75 kg. Baseline characteristics of the adult population by weight group (Table S1)
show that male patients were more likely to weigh >75 kg (50% vs 66.4%), but all the other
baseline characteristics were evenly distributed between the ≤75-kg and >75-kg groups,
respectively.

3.2 | Comparison of response rates between the weight-based dosing group and fixed
dose group
The difference and 95% confidence interval (CI) in the response rates for those ≤75 kg
versus those >75 kg were 3.1% (95% CI = −20.5% to 26.6%) for FOS, −1.2% (95% CI =
−21.6% to 19.3%) for LEV, and 6.4% (95% CI = −16.1% to 28.9%) for VPA. None of the
differences was statistically significant, as the 95% CI included 0 for each drug.
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3.3 | Association of weight and other predictors with primary outcome using univariate
and multivariate analyses
3.1.1 | Primary outcome versus weight—The odds of success were 10.1% lower
(odds ratio = 0.9, 95% CI = 0.54–1.51) for those >75 kg compared to those ≤75 kg and
15.4% lower (odds ratio = 0.85, 95% CI = 0.42–1.66) for those >90 kg compared to those
≤90 kg. These differences were not significant, as the 95% CIs for the odds ratios included
1. Similarly, there was no statistically significant association with treatment success when
sex, treatment group, and interaction of weight with sex and treatment group were included
in the model (Table 1).

3.3.2 | Primary outcome versus sex and weight-normalized dose—When each

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drug was modeled separately, the weight-normalized dose was not associated with success,
nor was sex or the interaction of dose and sex (Table S2).

3.4 | Association of weight, sex, and treatment with clinical seizure cessation without
additional antiseizure medication
A total of 138 (59%) patients did not have clinically apparent seizures at 60 minutes without
receiving additional antiseizure medication (regardless of whether they were responsive to

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verbal commands or noxious stimuli). As seen from Table 1, weight (≤ or >75 kg), sex (male
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or female), treatment group (FOS, LEV, or VPA), and all the interaction terms (weight × sex
× treatment group) did not have a significant association with clinical seizure cessation.

4| DISCUSSION
The results of these secondary analyses demonstrate that the differences in response rates
between the fixed dosing regimen (>75 kg) and weight-based regimen (≤75 kg) were not
significant when the study drugs were grouped together or analyzed separately. The logistic
regression models using the ESETT primary outcome and clinical seizure cessation without
additional antiseizure medication as dependent variables also failed to find significant
associations with weight, treatment, sex, or weight-normalized dose.

Fixed dosing, which is commonly used in adults, results in lower doses per body weight in
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heavier individuals and potentially lower drug concentrations for many drugs. Furthermore,
if drug concentrations fall in the linear portion of the dose-response curve, lower drug
concentrations may result in reduced efficacy. In this study, although approximately half
of the ESETT adult patients received the maximum dose, the response rates between weight-
based and fixed dosing regimen were similar. It is possible that weight or weight-normalized
dose did not affect the primary outcome or clinical seizure cessation because the doses
used in the trial resulted in drug concentrations greater than those needed for therapeutic
outcome even in patients weighing >75 kg. Although this may be true, other predictors,
such as drug concentration, would have been a better metric to evaluate the differences
between responders and nonresponders. We know that drug concentrations can be variable in
individuals receiving an identical dose.4–6 There is also evidence that the pharmacokinetics
of FOS, LEV, and VPA are altered in overweight and obese patients.7–10 In particular,
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patients with higher body fat will likely have greater volume of distribution. However, we
were not able to investigate the effect of drug concentrations or body mass index (BMI), as
sufficient information was not available. Furthermore, only 18 (7.7%) patients weighed >100
kg. Thus, differences in pharmacokinetics, if any, may not have been large enough to impact
the outcome.

The ESETT primary outcome was a composite and included absence of clinically apparent
seizures and improved responsiveness at 60 minutes. It is possible that those who received
higher doses were more likely to stop seizing but also more likely to have no improvement
in responsiveness. To tease out the association of weight and other variables with clinical
seizure cessation alone, we included those who failed the primary outcome only due to
the lack of improved responsiveness at 60 minutes as successes, but found no significant
differences between fixed and weight-based dosing. Future studies of SE will likely include
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electroencephalogram as a part of outcome and allow us to better understand this subgroup.

A limitation of these analyses is the small number of patients in each treatment group
(~40/drug) weighing >75 kg. The wide CIs for the difference in response rates suggest that
a larger sample size would be needed to confirm these findings. While these were secondary
analyses, the adaptive study design was powered adequately for the primary outcomes.

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5| CONCLUSION
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Weight-based dosing used in ESETT with a 75-kg cutoff does not appear to have an
impact on the primary outcome or clinical seizure cessation. It is possible that the
concentrations attained were greater than those needed for therapeutic outcome. However,
studies with larger sample size and additional data (drug concentrations, BMI, etc) are
required to confirm our findings. Future studies that measure drug concentrations would
allow exploration of exposure-response instead of dose-response relationships.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

ACKNOWLEDGMENTS
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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. Clinicaltrials.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
National Institute of Neurological Disorders and Stroke, Grant/Award Number: R01NS099653, U01NS056975,
U01NS059041, U01NS088023 and U01NS088034; College of Pharmacy, University of Minnesota

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FIGURE 1.
Distribution of Established Status Epilepticus Treatment Trial (ESETT) adult patient weights
and the response to the treatment administered as treatment success (blue) or treatment
failure (red)
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Table 1:

Logistic regression models of the probability of success using weight, treatment and sex with all interactions (weight ≤ 75 kg as reference group) (n=235)

Using primary outcome as dependent variable Using clinical seizure cessation without additional antiseizure medication as dependent variable
Weight-group Treatment Sex
Sathe et al.

Adjusted Odds Ratio (95% confidence interval) Adjusted Odds Ratio (95% confidence interval)
> 75 kg Fosphenytoin Male 0.71 (0.20, 2.55) 0.56 (0.14, 2.26)

> 75 kg Fosphenytoin Female 1.13 (0.26, 4.94) 1.16 (0.27, 5.05)

> 75 kg Levetiracetam Male 0.82 (0.26, 2.56) 0.47 (0.15, 1.49)

> 75 kg Levetiracetam Female 1.70 (0.45, 6.44) 1.08 (0.29, 4.08)

> 75 kg Valproic acid Male 0.83 (0.26, 2.66) 0.72 (0.22, 2.40)

> 75 kg Valproic acid Female 0.64 (0.14, 2.91) 0.49 (0.11, 2.20)

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