Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model

P. R. Territo, H. E. Shannon, K. Newhall, S. D. Barnhart, S. C. Peters, D. R. Engleking, T. Bin, T. J. Burnett, J. M. Rodewald, B. Abdul-Karim, K. J. Freise

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The anticonvulsant ameltolide (LY201116) is a novel potential therapy for the treatment of canine epilepsy. Eight dogs were administered five different oral doses of ameltolide and clinical scoring of the maximal electroshock (MES) induced seizures at 3 and 24 h postdosing were determined in two separate crossover design studies. Plasma ameltolide concentrations were determined at the time of seizures in all dogs and complete plasma concentration-time profiles were also determined in a separate study. A nonlinear mixed effects PK/PD model was fit to the resulting data. A one compartment open model with first order absorption was determined to best fit the ameltolide pharmacokinetics. An effect compartment with a cumulative logistic regression equation was used to establish the PK/PD relationship. The mean bioavailability normalized volume of distribution and the elimination half-life were estimated at 1.20 L/kg and 5.46 h, respectively. The fitted model estimated that from 2 to 15 h following a single 3 mg/kg oral ameltolide dose the mean probability of obtaining a 1 unit reduction in the seizure clinical score severity was greater than 0.80. The utilized PK/PD analysis combined with the canine MES model allowed for the rapid and efficient determination of the plasma ameltolide concentration- anticonvulsant relationship preclinically in dogs.

Original languageEnglish (US)
Pages (from-to)562-570
Number of pages9
JournalJournal of Veterinary Pharmacology and Therapeutics
Volume31
Issue number6
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • veterinary(all)

Fingerprint Dive into the research topics of 'Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model'. Together they form a unique fingerprint.

  • Cite this

    Territo, P. R., Shannon, H. E., Newhall, K., Barnhart, S. D., Peters, S. C., Engleking, D. R., Bin, T., Burnett, T. J., Rodewald, J. M., Abdul-Karim, B., & Freise, K. J. (2008). Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model. Journal of Veterinary Pharmacology and Therapeutics, 31(6), 562-570. https://doi.org/10.1111/j.1365-2885.2008.00995.x