Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures.
نویسندگان
چکیده
INTRODUCTION Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged ≥4 to <16 years as adjunctive treatment for focal (partial onset) seizures. The existing model described daily seizure counts using a negative binomial distribution, taking previous-day seizure frequencies into account, and using a mixture model to separate 'placebo-like' and 'responder' subpopulations. The model was adapted to describe aggregated monthly seizure counts for adult patients in the levetiracetam studies: daily seizure counts were only available for children in the levetiracetam studies. RESULTS The levetiracetam PK/PD model successfully described both the adult and pediatric data using the same drug effect parameters, and using a model structure similar to the existing adult brivaracetam PK/PD model. CONCLUSION Simulation with the adult brivaracetam PK/PD model in combination with an existing pediatric brivaracetam population PK model allowed characterization of the dose-response curve, suggesting maximum response at brivaracetam 4 mg/kg/day dosing (capped at 200 mg/day, the maximum adult dose) in children aged ≥4 years.
منابع مشابه
Response to “Response to Zhang et al.: Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta-analysis and indirect comparison”
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Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar m...
متن کاملResponse to Zhang et al.: Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta-analysis and indirect comparison
To the Editor, unmeasured confounding further undermines the validity of comparison between these trials. 6. Some of the studies in the meta-analysis included doses that were found to be non-therapeutic in the pivotal studies and have not been approved for clinical use (brivaracetam 5, 20 and 25 mg/day; levetiracetam 500 mg/day). As such, a brivaracetam dose of 5 mg/day should not be compared t...
متن کاملLevetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta-analysis and indirect comparison
PURPOSE The study aimed to compare the efficacy and tolerability of levetiracetam (LEV) and brivaracetam (BRV) in adults with refractory focal seizures. METHOD We systematically queried Medline, Embase, and the Cochrane Library. We looked for additional studies in the references of all identified publications and ClinicalTrials.gov. The cutoff day was November 6, 2015. Randomized, double-blin...
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عنوان ژورنال:
- Clinical pharmacokinetics
دوره شماره
صفحات -
تاریخ انتشار 2017