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

Paul 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 Citation (Scopus)

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 2008
Externally publishedYes

Fingerprint

ameltolide
anticonvulsants
pharmacology
seizures
Anticonvulsants
pharmacokinetics
Canidae
Seizures
Pharmacokinetics
dogs
Electroshock
mouth
Dogs
Cross-Over Studies
epilepsy
dosage
half life
bioavailability
Biological Availability
Half-Life

ASJC Scopus subject areas

  • Pharmacology
  • veterinary(all)

Cite this

Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model. / Territo, Paul; 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.

In: Journal of Veterinary Pharmacology and Therapeutics, Vol. 31, No. 6, 12.2008, p. 562-570.

Research output: Contribution to journalArticle

Territo, P, Shannon, HE, Newhall, K, Barnhart, SD, Peters, SC, Engleking, DR, Bin, T, Burnett, TJ, Rodewald, JM, Abdul-Karim, B & Freise, KJ 2008, 'Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model', Journal of Veterinary Pharmacology and Therapeutics, vol. 31, no. 6, pp. 562-570. https://doi.org/10.1111/j.1365-2885.2008.00995.x
Territo, Paul ; 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. / Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model. In: Journal of Veterinary Pharmacology and Therapeutics. 2008 ; Vol. 31, No. 6. pp. 562-570.
@article{e1631adc04ab4998b75f69dd32167093,
title = "Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model",
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.",
author = "Paul Territo and Shannon, {H. E.} and K. Newhall and Barnhart, {S. D.} and Peters, {S. C.} and Engleking, {D. R.} and T. Bin and Burnett, {T. J.} and Rodewald, {J. M.} and B. Abdul-Karim and Freise, {K. J.}",
year = "2008",
month = "12",
doi = "10.1111/j.1365-2885.2008.00995.x",
language = "English (US)",
volume = "31",
pages = "562--570",
journal = "Journal of Veterinary Pharmacology and Therapeutics",
issn = "0140-7783",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model

AU - Territo, Paul

AU - Shannon, H. E.

AU - Newhall, K.

AU - Barnhart, S. D.

AU - Peters, S. C.

AU - Engleking, D. R.

AU - Bin, T.

AU - Burnett, T. J.

AU - Rodewald, J. M.

AU - Abdul-Karim, B.

AU - Freise, K. J.

PY - 2008/12

Y1 - 2008/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=55949132877&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55949132877&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2885.2008.00995.x

DO - 10.1111/j.1365-2885.2008.00995.x

M3 - Article

C2 - 19000280

AN - SCOPUS:55949132877

VL - 31

SP - 562

EP - 570

JO - Journal of Veterinary Pharmacology and Therapeutics

JF - Journal of Veterinary Pharmacology and Therapeutics

SN - 0140-7783

IS - 6

ER -