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.
authors.affiliation: Lilly Center for Molecular and Anatomical Imaging, Lilly Research Laboratories, A Division(s) of Eli Lilly and Company, Greenfield, IN 46140, USA. territop@lilly.com
authors.forename: P R
authors.initials: PR
authors.lastname: Territo
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: K
authors.initials: K
authors.lastname: Newhall
authors.forename: S D
authors.initials: SD
authors.lastname: Barnhart
authors.forename: S C
authors.initials: SC
authors.lastname: Peters
authors.forename: D R
authors.initials: DR
authors.lastname: Engleking
authors.forename: T
authors.initials: T
authors.lastname: Bin
authors.forename: T J
authors.initials: TJ
authors.lastname: Burnett
authors.forename: J M
authors.initials: JM
authors.lastname: Rodewald
authors.forename: B
authors.initials: B
authors.lastname: Abdul-Karim
authors.forename: K J
authors.initials: KJ
authors.lastname: Freise
mesh_terms: D000042:Absorption; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001549:Benzamides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D004285:Dogs; D006207:Half-Life; D016015:Logistic Models; D008297:Male; D017711:Nonlinear Dynamics; D012640:Seizures / Q000517:prevention & control; D014018:Tissue Distribution
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; C055323:ameltolide