Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 56, Issue 12, Pages 1591-1602Publisher
WILEY
DOI: 10.1002/jcph.761
Keywords
brivaracetam; SV2A; epilepsy; concentration-effect relationship; daily seizure counts; nonlinear mixed-effects modeling; nonmem
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Funding
- UCB Pharma
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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.
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