Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

Selioutski, Olga; Grzesik, Katherine; Vasilyeva, O.N.; Hilmarsson, Ágúst; Fessler, A. James; Liu, Lynn; Gross, Robert A.

doi:10.1016/j.seizure.2017.10.006

Cited by 13 publications

(13 citation statements)

References 19 publications

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“…12 Similarly, PHT concentrations, both unbound and total, were consistent with previously published reports. [19][20][21][22][23] It is worth noting that in our study the concentrations in 3 patients (5 samples) randomly assigned to LEV and 1 patient (2 samples) randomized to VPA may have been affected by the use of the respective randomized drug as chronic oral therapy.…”

Section: Discussionmentioning

confidence: 80%

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Sathe

Mishra

Ivaturi

et al. 2021

The Journal of Clinical Pharma

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Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepinerefractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

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Section: Discussionmentioning

confidence: 80%

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Sathe

Mishra

Ivaturi

et al. 2021

The Journal of Clinical Pharma

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“…A recent study evaluated postload total phenytoin concentrations, whereby targeted concentrations were ≥20.0 µg/mL. 16 This was a retrospective study involving 494 patients who had a median weight of 75 kg. For patients receiving phenytoin LDs of 15 to 20 mg/kg, 63% did not achieve a total phenytoin concentration of >20 µg/mL when measured within 6 hours of administration.…”

Section: Discussionmentioning

confidence: 99%

“…15 Whereas manufacturers recommend a goal for the free concentrations of 1 to 2 mg/L, others support peak concentrations >2 mg/L. 1,2,16 Pharmacokinetically, the average volume of distribution of phenytoin is 0.65 L/kg. 17 Thus, LDs of 10 to 25 mg/kg in an average-weight patient would be expected to achieve peak concentrations ranging from 15.4 to 38.5 mg/L, with corresponding free phenytoin concentrations of 1.5 to 3.9 mg/L.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex

2018

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Background: Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese. Objectives: To examine the influence of obesity and sex on phenytoin LDs. Methods: This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated. Results: There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 µg/mL [IQR = 1.4-2.0]; nonobese: 1.8 µg/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 µg/mL [IQR = 1.2-2.1]; female: 1.7 µg/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.

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“…However, this finding has been previously supported and the authors have recommended avoidance of preset PHT LDs. 22 This trend is further explained in a study by Brancaccio et al, 23 which suggested that a fixed dosing strategy of 1000 mg may be used because of prescriber familiarity; however, with the rates of obesity increasing, this approach may lead to a large proportion of patients failing to achieve therapeutic concentrations, subsequently impacting patient outcomes. Interestingly, Brancaccio et al explored the impact of a PHT LD program, which was further stratified into pharmacist-led and prescriber-led.…”

Section: Discussionmentioning

confidence: 99%

Critical Care Management of Status Epilepticus at a Tertiary Care University Hospital

Mahmoud

Marette

Lindqvist

et al. 2019

Can. J. Neurol. Sci.

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ABSTRACT:Background:Status epilepticus (SE) is a neurological emergency associated with significant morbidity and mortality. The objective of this study was to review the critical care management of patients with SE focusing on antiepileptic drugs (AEDs) as well as to determine the optimal dosing strategies of phenytoin (PHT) and predictors of its effectiveness.Methods:A retrospective chart review of adult patients with SE admitted to the University of Alberta Hospital, Canada, was conducted.Results:Fifty-six admissions were included. Benzodiazepines (BDZs) were initially given in 89% of our patients. Following BDZs, PHT and levetiracetam were the most commonly initiated AEDs as first- and second-line agents and were deemed effective in 30/44 and 5/11 patients, respectively. Patients who received a PHT loading dose (LD) of 1000 mg were less likely to reach target levels compared with a weight-based LD ≥15 mg/kg (29% vs. 60%). Likewise, patients who received a maintenance dose (MD) of 300 mg/day were less likely to reach target compared with 400 mg/day or >5 mg/kg per day; however, this did not reach statistical significance. Three variables were found to be associated with PHT effectiveness: tonic-clonic SE (OR 5.01, 95% CI 1.02–24.7, p = 0.048), history of seizures and BMI <30 kg/m2 (OR 0.16, 95% CI 0.03–1.07, p = 0.059).Conclusions:Further studies of the predictors of PHT effectiveness, specifically obesity, are necessary to help individualize care. Finally, we suggest that PHT should be loaded according to the guidelines as 20 mg/kg followed by an MD of at least 400 mg/day or >5 mg/kg per day.

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Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

Cited by 13 publications

References 19 publications

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex

Critical Care Management of Status Epilepticus at a Tertiary Care University Hospital

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