Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model
| Autor: | K. Newhall, J. M. Rodewald, D. R. Engleking, B. Abdul-Karim, T. J. Burnett, Harlan E. Shannon, K. J. Freise, P. R. Territo, T. Bin, S. C. Peters, S. D. Barnhart |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_treatment Biological Availability Pharmacology Absorption Epilepsy Dogs Pharmacokinetics Seizures medicine Animals Tissue Distribution Volume of distribution General Veterinary Chemistry Half-life Ameltolide medicine.disease Crossover study Bioavailability Anticonvulsant Logistic Models Nonlinear Dynamics Area Under Curve Benzamides Anticonvulsants Half-Life |
| Zdroj: | Journal of veterinary pharmacology and therapeutics. 31(6) |
| ISSN: | 1365-2885 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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