Chemical formula: C₁₇H₁₆N₂O₃ Molecular mass: 254.284 g/mol
The precise mechanisms of action of eslicarbazepine acetate are unknown. However, in vitro electrophysiological studies indicate that both eslicarbazepine acetate and its metabolites stabilise the inactivated state of voltage-gated sodium channels, precluding their return to the activated state and thereby preventing repetitive neuronal firing.
Eslicarbazepine acetate and its active metabolites prevented the development of seizures in nonclinical models predictive of anticonvulsant efficacy in man. In humans, the pharmacological activity of eslicarbazepine acetate is primarily exerted through the active metabolite eslicarbazepine.
Eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Bioavailability may be assumed as high because the amount of metabolites recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose.
The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent from concentration. In vitro studies have shown that plasma protein binding was not relevantly affected by the presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide. The binding of warfarin, diazepam, digoxin, phenytoin and tolbutamide was not significantly affected by the presence of eslicarbazepine.
Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metabolite eslicarbazepine by hydrolytic first-pass metabolism. The steady state plasma concentrations are attained after 4 to 5 days of once daily dosing, consistent with an effective half-life in the order of 20-24 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of eslicarbazepine was 10-20 hours and 13-20 hours, respectively. Minor metabolites in plasma are Rlicarbazepine and oxcarbazepine, which were shown to be active, and the glucuronic acid conjugates of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine and oxcarbazepine.
Eslicarbazepine acetate does not affect its own metabolism or clearance.
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19.
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated glucuronidation was observed.
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion, in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide correspond to more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and one third as glucuronide conjugate.
The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 400-1,200 mg both in healthy subjects and patients.
The pharmacokinetic profile of eslicarbazepine acetate is unaffected in the elderly patients with creatinine clearance >60 ml/min.
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion. A study in adult patients with mild to severe renal impairment showed that clearance is dependent on renal function. During treatment with eslicarbazepine dose adjustment is recommended in patients, adult and children above 6 years of age with creatinine clearance <60 ml/min.
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age the intrinsic activity of the elimination process has not yet reached maturation.
Haemodialysis removes eslicarbazepine acetate metabolites from plasma.
The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy subjects and moderately liver-impaired patients after multiple oral doses. Moderate hepatic impairment did not affect the pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended in patients with mild to moderate liver impairment. The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic impairment.
Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine acetate were not affected by gender.
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an effect on volume of distribution and clearance. Furthermore, a role of age independently of weight with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the youngest age group (2-6 years).
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age.
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of eslicarbazepine acetate once-daily, respectively.
Adverse reactions observed in animal studies occurred at exposure levels appreciably lower than the clinical exposure levels to eslicarbazepine (the principal and pharmacologically active metabolite of eslicarbazepine acetate). Safety margins based on comparative exposure have thus not been established.
Evidence of nephrotoxicity was observed in repeated dose-toxicity studies in the rat, but was not seen in studies in mice or dogs, and is consistent with an exacerbation of spontaneous chronic progressive nephropathy in this species.
Liver centrilobular hypertrophy was seen in repeated-dose toxicity studies in mice and rats and an increased incidence of liver tumours was observed in the carcinogenicity study in mice; these findings are consistent with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients receiving eslicarbazepine acetate.
In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult animals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineral density in lumbar vertebrae and/or femur were observed in high-dose female animals at exposure levels lower than the clinical exposure levels to eslicarbazepine in children.
Genotoxicity studies with eslicarbazepine acetate indicate no special hazards for humans.
Impairment of fertility was observed in female rats; decreases in implantations and live embryos seen in the mouse fertility study may also indicate effects on female fertility, however, corpora lutea counts were not evaluated. Eslicarbazepine acetate was not teratogenic in the rat or rabbit, but did induce skeletal abnormalities in the mouse. Ossification delays, reduced foetal weights, an increase in minor skeletal and visceral anomalies were observed at maternal toxic doses in embryotoxicity studies in mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in peri/postnatal studies in mice and rats.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
