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Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus.

AbstractOBJECTIVE:
Canine status epilepticus (CSE) has potential as a translational platform to evaluate the safety and efficacy of novel compounds and inform human status epilepticus trials. The aim of this study was to determine the intravenous dose of fosphenytoin (FOS) needed for dogs in a CSE clinical trial to attain phenytoin (PHT) concentrations similar to those used for human status epilepticus and monitor PHT concentrations.
METHODS:
Four healthy dogs were used to characterize PHT pharmacokinetics. Each received either 15 mg/kg or 25 mg/kg of PHT equivalent intravenously. Blood samples were collected and FOS (total) and derived PHT (total and unbound) plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Noncompartmental pharmacokinetics (PK) parameter values were determined and compartmental PK modeling and simulations were used to select the dose for the clinical trial with a target goal of 1-2 μg/ml unbound PHT at 30-60 min postinfusion. Predicted total and unbound PHT concentrations were compared with concentrations in blood collected from dogs treated for CSE in the clinical trial.
RESULTS:
Initial estimates suggested that a loading dose of 25 mg/kg would attain unbound concentrations of 1-2 μg/ml; however, this dose produced concentrations above 3-6 μg/ml, which resulted in clinically significant toxicity. A two-compartment model best fit the PHT concentration data with alpha-phase half-life of 2-5 min and elimination half-life of ~5 h. Based on the simulations, a dose of 15 mg/kg was selected and used in the clinical trial and 15 of 16 dogs randomized to the treatment arm had PHT plasma concentrations within the goal range.
SIGNIFICANCE:
This study demonstrates that characterization of pharmacokinetics in a small number of dogs is useful in determining dosage regimens designed to attain targeted concentrations in clinical trials. Using this approach, we were able to determine a safe and effective dose of FOS for a clinical trial of CSE.
AuthorsLisa D Coles, Ilo E Leppik, Edward E Patterson, Zachary Rivers, Usha Mishra, James C Cloyd
JournalEpilepsia (Epilepsia) Vol. 56 Issue 6 Pg. 888-94 (Jun 2015) ISSN: 1528-1167 [Electronic] United States
PMID25952988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightWiley Periodicals, Inc. © 2015 International League Against Epilepsy.
Chemical References
  • Anticonvulsants
  • Phenytoin
  • fosphenytoin
Topics
  • Administration, Intravenous
  • Animals
  • Anticonvulsants (administration & dosage, pharmacokinetics)
  • Area Under Curve
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Linear Models
  • Male
  • Phenytoin (administration & dosage, analogs & derivatives, blood, pharmacokinetics)
  • Time Factors

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