Population pharmacokinetics of the new antiepileptic drug brivaracetam
Hussein, Ziad(1), Brigitte Lacroix(2), Maria-Laura Sargentini-Maier(2)
(1) Medeval Ltd, Manchester UK; (2) UCB S.A., Braine L'Alleud, Belgium
Objectives: Characterization of population pharmacokinetics of the new antiepileptic drug brivaracetam (ucb 34714) in healthy and epileptic adult populations from clinical pharmacology , in order to identify possible covariates that may have an influence on the pharmacokinetics (PK) of brivaracetam
Methods: 203 subjects received a single dose or b.i.d. doses (3 days to 4 weeks) of brivaracetam in 12 clinical pharmacology studies. Brivaracetam concentration-time data were analyzed using nonlinear mixed-effect modeling (NONMEM). Food intake, age, gender, body weight, body surface area (BSA), dose, duration of treatment, use of concomitant AEDs, health status and creatinine clearance (CLcr) were examined as possible covariates to explain inter-individual variability in PK parameters of brivaracetam.
Results: Of the 203 subjects, 187 were Caucasian, 62 female, 9 severely renally impaired, 15 elderly and 28 epileptic subjects, with the following respective means (range) for weight, BSA, age and CLcr: 72 (44-124) kg, 1.86 (1.37-2.43) m², 34 (18-79) years and 100 (13-170) mL/min. Brivaracetam plasma concentrations were adequately described by a one -compartment model, with low residual variability (11.5% CV). Weight, gender, age and concomitant inducing AEDs were identified as covariates affecting CL/F resulting in a reduction of inter-individual variability (IIV) from 23% to 15%. The population mean of CL/F was estimated to be 3.84 L/h and 3.14 L/h for males and females, respectively (28 years and 73 kg) in absence of inducers. Concomitant AEDs inducers increased CL/F by 26%. Weight and gender were identified as covariates on V/F resulting in a reduction of IIV from 14% to 9%. The population mean of V/F was 0.55 L/kg and 0.48 L/kg for males and females, respectively.
Conclusions: Most of the inter-individual variability in brivaracetam pharmacokinetics was accounted for by differences in weight, gender, age and concomitant AEDs. Since the identified covariates had a modest influence on PK parameters, brivaracetam is deemed to have a highly predictable exposure in individual subjects. Results suggest that no dose-adjustment is required. The current model can be used to predict exposure in target populations in phase 2/3 studies.