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

Abhishek G. Sathe, Usha Mishra, Vijay Ivaturi, Richard C. Brundage, James C. Cloyd, Jordan J. Elm, James M. Chamberlain, Robert Silbergleit, Jaideep Kapur, Daniel H. Lowenstein, Shlomo Shinnar, Hannah R. Cock, Nathan B. Fountain, Lynn Babcock, Lisa D. Coles

Research output: Contribution to journalArticlepeer-review

Abstract

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 benzodiazepine-refractory 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.

Original languageEnglish (US)
Pages (from-to)763-768
Number of pages6
JournalJournal of Clinical Pharmacology
Volume61
Issue number6
DOIs
StatePublished - Jun 2021

Bibliographical note

Funding Information:
Research reported in this publication was supported by National Institutes of Health, National Institutes of Neurological Disorders and Stroke, under Awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653 (clinicaltrials.gov identifier NCT01960075). The authors thank 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 publication was supported by National Institutes of Health, National Institutes of Neurological Disorders and Stroke, under Awards U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653 (clinicaltrials.gov identifier NCT01960075).

Funding Information:
Dr. Sathe, Ms. Mishra, Dr. Ivaturi, Dr. Brundage, Dr. Lowenstein, Dr. Babcock, and Dr. Coles declare no conflicts of interest. Dr. Cloyd reports licensing fees from Ligand, personal fees from UCB, and grants and personal fees from Neurelis, that are outside the submitted work. In addition, Dr. Cloyd has an issued patent for intravenous carbamazepine and a pending patent on intravenous topiramate with royalties paid by Ligand. Dr. Elm reports grants from the National Institutes of Health (NIH)/NINDS, during the conduct of the study. Dr. Chamberlain reports grants from NIH during the conduct of the study. Dr. Silbergleit reports grants from NIH during the conduct of the study. Dr. Kapur reports grants from NIH/NINDS during the conduct of the study. Dr. Shinnar reports grants from NINDS, during the conduct of the study; personal fees from UCB Pharma, personal fees from Eisai, outside the submitted work. Dr. Cock reports personal fees from Sage Pharmaceuticals Ltd, personal fees from Bial Pharma UK, Eisai Europe Ltd, personal fees from UCB Pharma Ltd, non‐financial support from Special Products Ltd, other from Novartis, other from GWPharma, outside the submitted work. Dr. Fountain reports grants from NIH, during the conduct of the study; grants from UCB, grants from SK Life Sciences, grants from Xenon, grants from GW Pharma, and grants from DSLP, outside the submitted work.

Publisher Copyright:
© 2020, The American College of Clinical Pharmacology

Keywords

  • central nervous system (CNS)
  • clinical pharmacology (CPH)
  • clinical trials (CTR)
  • emergency medicine (EME)
  • exposure-response
  • neurology (NEU)
  • pediatrics (PED)
  • pharmacokinetics and drug metabolism
  • protein binding
  • sparse sampling

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Fingerprint

Dive into the research topics of 'Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus'. Together they form a unique fingerprint.

Cite this