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Safety, Tolerability, and Pharmacokinetic Profile of BIA 2‐093, a Novel Putative Antiepileptic, in a Rising Multiple‐Dose Study in Young Healthy Humans
Author(s) -
Almeida Luis,
SoaresdaSilva Patrício
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270004267591
Subject(s) - pharmacokinetics , dosing , tolerability , placebo , metabolite , dose , pharmacology , oral administration , medicine , urine , antiepileptic drug , adverse effect , epilepsy , alternative medicine , pathology , psychiatry
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‐τ (day 8)/AUC 0‐τ (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.