Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate.
OBJECTIVE
Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development.


METHODS
ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n=8, control group), and in patients with mild renal impairment (n=8), moderate renal impairment (n=8), severe renal impairment (n=8), and end-stage renal disease requiring hemodialysis (n=8).


RESULTS
ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation.


CONCLUSIONS
ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance <60 ml/min.
Maia
J
J
Department of Research and Development, BIAL (Portela & Ca SA), S. Mamede do Coronado, Portugal.
Almeida
L
L
Falcão
A
A
Soares
E
E
Mota
F
F
Potgieter
M A
MA
Potgieter
J H
JH
Soares-da-Silva
P
P
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D003984:Dibenzazepines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D051437:Renal Insufficiency / Q000378:metabolism*
D000927:Anticonvulsants; D003984:Dibenzazepines; C416835:eslicarbazepine acetate