Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers

Epilepsia. 2013 Aug;54(8):1453-61. doi: 10.1111/epi.12242. Epub 2013 Jun 12.

Abstract

Purpose: Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers.

Methods: Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers.

Key findings: Mean eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0-τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively.

Significance: ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss ) of eslicarbazepine and similar extent of plasma exposure (AUCss,0-τ ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

Keywords: Eslicarbazepine acetate; Healthy volunteers; Once-daily; Oxcarbazepine; Pharmacokinetics; Tolerability; Twice-daily.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anticonvulsants / blood
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / urine
  • Area Under Curve
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / blood
  • Carbamazepine / chemistry
  • Carbamazepine / pharmacokinetics
  • Carbamazepine / urine
  • Chromatography, High Pressure Liquid
  • Cross-Over Studies
  • Dibenzazepines / blood
  • Dibenzazepines / chemistry
  • Dibenzazepines / pharmacokinetics*
  • Dibenzazepines / urine
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Electrochemistry
  • Female
  • Heart Rate / drug effects
  • Humans
  • Male
  • Oxcarbazepine
  • Time Factors

Substances

  • Anticonvulsants
  • Dibenzazepines
  • Carbamazepine
  • eslicarbazepine acetate
  • Oxcarbazepine