Population Pharmacokinetics of Brivaracetam in Patients with Partial Epilepsy
Brigitte Lacroix(1), Philipp von Rosenstiel(2), Maria Laura Sargentini-Maier(1)
(1)Pharmacometrics, Global Exploratory Development, UCB Pharma SA, Braine-l’Alleud, Belgium; (2)UCB Inc, Smyrna, GA, USA
Objectives: To model the population pharmacokinetics of brivaracetam (BRV), a novel antiepileptic drug (AED) in development, in refractory patients with partial epilepsy, in order to identify potential demographic and drug interaction covariates.
Methods: Adult patients with refractory partial-onset seizures received adjunctive BRV BID during 7 to 10 weeks in 2 double-blind, placebo-controlled, parallel-group, dose-ranging studies. The dose levels were 5, 20, 50 mg/day and 50, 150 mg/day in 2 intakes. 2 plasma samples per visit were obtained on 2 to 4 occasions between weeks 3 and 10. BRV concentration-time data were modeled using nonlinear mixed-effect modeling (NONMEM). Bodyweight was included in the base model as an allometric factor of clearance (CL/F) and distribution volume (V/F). Age, gender, race, concomitant AEDs and creatinine clearance (CLcr) were examined as possible covariates to explain inter-individual variability in pharmacokinetic parameters of BRV.
Results: 1150 concentration-time records were available in 254 patients (50% male; 60% caucasian) receiving 1 or 2 concomitant AEDs (39 neutral, 98 inducer, 77 inhibitor, and 40 mixed inhibitor/inducer). The mean (range) for weight, age and CLcr was 70 (24-129) kg, 34 (16-65) years and 122 (39-253) mL/min. BRV plasma concentrations were adequately described by a one-compartment model, with low residual variability (20.0% CV). Age, gender, race and CLcr did not influence the pharmacokinetic parameters of BRV. The population mean for V/F was 0.51 L/kg. Concomitant intake of inducer AEDs was a significant covariate for CL/F, resulting in a reduction of inter-individual variability (IIV) from 31% to 24%. The population mean of CL/F was estimated to be 3.63 L/h in absence and 5.15 L/h in presence of inducer AEDs. This effect was predicted to decrease the steady-state AUC of BRV by ~30%. This moderate exposure reduction is likely to be of little clinical relevance, because a dose-response analysis of phase II trial data showed that concomitant inducer AEDs did not influence BRV's efficacy.
Conclusions: Most of the inter-individual variability in BRV pharmacokinetics, in an ethnically diverse population of patients, was accounted for by differences in bodyweight and concomitant use of inducer AEDs. Since the identified covariates had a modest influence on pharmacokinetic parameters, BRV is deemed to have a highly predictable exposure in individual subjects. Results suggest that no dose adjustment is required.