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

J Clin Pharmacol. 2021 Jun;61(6):763-768. doi: 10.1002/jcph.1801. Epub 2021 Jan 12.


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.

Trial registration: ClinicalTrials.gov NCT01960075.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anticonvulsants / administration & dosage
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / therapeutic use*
  • Benzodiazepines / therapeutic use
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Infusions, Intravenous
  • Levetiracetam / administration & dosage
  • Levetiracetam / pharmacokinetics
  • Male
  • Phenytoin / administration & dosage
  • Phenytoin / analogs & derivatives
  • Phenytoin / pharmacokinetics
  • Protein Binding
  • Status Epilepticus / drug therapy*
  • Valproic Acid / administration & dosage
  • Valproic Acid / pharmacokinetics


  • Anticonvulsants
  • Benzodiazepines
  • Levetiracetam
  • Valproic Acid
  • Phenytoin
  • fosphenytoin

Associated data

  • ClinicalTrials.gov/NCT01960075