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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Objective 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.

Original languageEnglish (US)
Pages (from-to)888-894
Number of pages7
JournalEpilepsia
Volume56
Issue number6
DOIs
StatePublished - Jan 1 2015

Fingerprint

Status Epilepticus
Phenytoin
Canidae
Pharmacokinetics
Clinical Trials
Dogs
Half-Life
fosphenytoin
Mass Spectrometry
High Pressure Liquid Chromatography
Safety

Keywords

  • Dog
  • Epilepsy
  • Phenytoin
  • Seizure
  • Translational

Cite this

@article{cfad5a1754274055b80f45cfc5b1ab1b,
title = "Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus",
abstract = "Objective 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.",
keywords = "Dog, Epilepsy, Phenytoin, Seizure, Translational",
author = "Coles, {Lisa D} and Leppik, {Ilo E} and Ned Patterson and Zachary Rivers and Usha Mishra and Cloyd, {James C}",
year = "2015",
month = "1",
day = "1",
doi = "10.1111/epi.12961",
language = "English (US)",
volume = "56",
pages = "888--894",
journal = "Epilepsia",
issn = "0013-9580",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus

AU - Coles, Lisa D

AU - Leppik, Ilo E

AU - Patterson, Ned

AU - Rivers, Zachary

AU - Mishra, Usha

AU - Cloyd, James C

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Objective 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.

AB - Objective 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.

KW - Dog

KW - Epilepsy

KW - Phenytoin

KW - Seizure

KW - Translational

UR - http://www.scopus.com/inward/record.url?scp=84930474306&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930474306&partnerID=8YFLogxK

U2 - 10.1111/epi.12961

DO - 10.1111/epi.12961

M3 - Article

C2 - 25952988

AN - SCOPUS:84930474306

VL - 56

SP - 888

EP - 894

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 6

ER -