Epilepsia · 2012
Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers.
Клиническое исследование I фазыСтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Nunes Teresa, Rocha José Francisco, Falcão Amílcar, Almeida Luis, Soares-da-Silva Patrício
Аннотация
PURPOSE: 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.
KEY FINDINGS: 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.
SIGNIFICANCE: 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.
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.
KEY FINDINGS: 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.
SIGNIFICANCE: 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.