title: Brivaracetam Population Pharmacokinetics and Exposure-Response Modeling in Adult Subjects With Partial-Onset Seizures.
abstract: Brivaracetam is a selective high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of partial-onset (focal) seizures in patients 16 years of age and older with epilepsy. A population pharmacokinetic (PK) model and a population pharmacokinetic/pharmacodynamic (PKPD) model were developed describing brivaracetam plasma concentration and the relationship with daily seizure counts in adequate well-controlled efficacy trials. The effect of body weight on clearance and volume was implemented using allometric scaling, and a range of covariates were investigated for their influence on brivaracetam clearance. The PKPD model described daily seizure counts using a negative binomial distribution, taking previous day seizures into account, and using a mixture model to separate "placebo-like" and "response" subpopulations. The PK and PKPD models provided a good description of the data, documented using visual predictive checks. Coadministration with carbamazepine, phenytoin, and phenobarbital decreased brivaracetam exposure by 26%, 21%, and 19%, respectively, without significant effects on PD response. Covariate analysis indicated that levetiracetam coadministration reduced the fraction of subjects in the mixture model response population to 4% and identified baseline seizure frequency as a strong predictor for being assigned to the mixture model response population. Simulation allowed characterization of the dose-response curve, suggesting maximum response is obtained at brivaracetam 150-200 mg/day.
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.|Current affiliation: Occams, Amstelveen, Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: Schoemaker
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.|Current affiliation: Occams, Amstelveen, Netherlands.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Wade
authors.affiliation: UCB Pharma, Braine l'Alleud, Belgium.
authors.forename: Armel
authors.initials: A
authors.lastname: Stockis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011760:Pyrrolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam
keywords: SV2A; brivaracetam; concentration-effect relationship; daily seizure counts; epilepsy; nonlinear mixed-effects modeling; nonmem