title: Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.
abstract: Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.
authors.affiliation: Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA.
authors.forename: Jace C
authors.initials: JC
authors.lastname: Nielsen
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hutmacher
authors.forename: David L
authors.initials: DL
authors.lastname: Wesche
authors.forename: Dwain
authors.initials: D
authors.lastname: Tolbert
authors.forename: Mahlaqa
authors.initials: M
authors.lastname: Patel
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Kowalski
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012640:Seizures / Q000188:drug therapy*; D020888:Vigabatrin / Q000008:administration & dosage* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D020888:Vigabatrin
keywords: dose response; epilepsy; pharmacology; population modeling; vigabatrin