Steady‐state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers

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.