Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers.
OBJECTIVE
To evaluate the pharmacokinetics and tolerability of once-daily eslicarbazepine acetate (ESL) and twice-daily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration.


METHODS
Single-center, open-label, randomized, parallel-group study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1-3 and 1,200 mg on days 4-9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1-3 and 600 mg on days 4-9, twice daily. Plasma and CSF sampling was performed following the last dose.


RESULTS
Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R-licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively.


CONCLUSIONS
In comparison to OXC, administration of ESL resulted in more eslicarbazepine, less R-licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supports once-daily dosing of ESL.
Department of Research and Development, BIAL - Portela & Ca. SA, S. Mamede do Coronado, Portugal.
Teresa
T
Nunes
José Francisco
JF
Rocha
Amílcar
A
Falcão
Luis
L
Almeida
Patrício
P
Soares-da-Silva
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D003984:Dibenzazepines / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
D000927:Anticonvulsants; D003984:Dibenzazepines; C476610:oxcarbamazepine; D002220:Carbamazepine; C416835:eslicarbazepine acetate; C428744:10,11-dihydro-10-hydroxy-5H-dibenz(b,f)azepine-5-carboxamide