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.

• Authors: 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
• Journal: Journal of veterinary pharmacology and therapeutics (J Vet Pharmacol Ther) Vol. 31 Issue 6 Pg. 562-70 (Dec 2008) ISSN: 1365-2885 [Electronic] England
• PMID: 19000280 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Benzamides
• ameltolide

Topics

• Absorption
• Animals
• Anticonvulsants (pharmacokinetics, pharmacology, therapeutic use)
• Area Under Curve
• Benzamides (pharmacokinetics, pharmacology, therapeutic use)
• Biological Availability
• Dogs
• Half-Life
• Logistic Models
• Male
• Nonlinear Dynamics
• Seizures (prevention & control)
• Tissue Distribution