Abstracts

Rationale: Population pharmacokinetics (PK) is useful to characterize the kinetic profile of a drug in the target population. The aim of this analysis is to investigate the population PK of eslicarbazepine (the major active metabolite of eslicarbazepine acetate, ESL) in patients with partial-onset seizures and to assess the possible effect of concomitant anti-epileptic therapy on eslicarbazepine kinetics. Methods: Data collected from 641 patients who participated in three Phase 3 studies with sparse sampling and from a sub-study in 51 patients with intense serial sampling were used in the analysis. Multiple once-daily doses (400 mg to 1200 mg/day) of ESL were administered. Concentration-time data were modelled using NONMEM to estimate eslicarbazepine PK parameters as well as the influence of several demographic and clinical covariates. Results: Subjects were between the ages of 17-76 years. Eslicarbazepine PK was best described by a one compartment open body model, with a first order absorption (absorption rate constant, ka=1.25 h-1). The basal apparent clearance (CL/F) was 3.82 L/h (37% inter-patient variability). Eslicarbazepine CL/F was unaffected by dose, gender, age, and laboratory safety parameters (AST, ALT, ALP and creatinine). No time dependency was observed in eslicarbazepine PK for up to one year of treatment. Eslicarbazepine CL/F was also unaffected by concomitant administration of lamotrigine, valproate, topiramate, gabapentin, clobazam and levetiracetam. CL/F was dependent on patient’s weight and was increased by carbamazepine and phenobarbital. Conclusions: Eslicarbazepine PK was found to be linear and predictable, independent of the concomitant administration of several AEDs, laboratory safety parameters, age and gender. PK had limited variability and was only affected by known strong metabolic inducers (carbamazepine and phenobarbital). Lamotrigine, valproate, topiramate, gabapentin, clobazam and levetiracetam were not found to affect the exposure to ESL. Support: BIAL - Portela & Co, SA