Safety, tolerability, and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans

J Clin Pharmacol. 2004 Aug;44(8):906-18. doi: 10.1177/0091270004267591.

Abstract

This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / adverse effects
  • Anticonvulsants / pharmacokinetics*
  • Area Under Curve
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / blood
  • Carbamazepine / urine
  • Dibenzazepines / administration & dosage
  • Dibenzazepines / adverse effects
  • Dibenzazepines / blood
  • Dibenzazepines / pharmacokinetics*
  • Dibenzazepines / urine
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Oxcarbazepine
  • Tablets

Substances

  • Anticonvulsants
  • Dibenzazepines
  • Tablets
  • Carbamazepine
  • eslicarbazepine acetate
  • Oxcarbazepine
  • 10,11-dihydro-10-hydroxy-5H-dibenz(b,f)azepine-5-carboxamide