Trileptal Mechanism of Action





Full Prescribing Info
ATC Code: N03A F02.
Pharmacology: Mechanism of Action: The pharmacological activity of Trileptal (oxcarbazepine) is mediated principally by the MHD metabolite (monohydroxy derivative of oxcarbazepine). It is assumed that the mechanism of action of oxcarbazepine and MHD primarily lies in the blockade of voltage-sensitive sodium channels, which leads to stabilization of overly excitable neuronal membranes, inhibition of repetitive neuronal discharges and slowing down of the synaptic propagation of excitatory impulses. An increased inflow of potassium and the modulation of high-voltage-activated calcium channels may also contribute to the anticonvulsant effect of the drug. No significant interactions with brain neurotransmitter or modulator receptor sites have been found.
Pharmacodynamics: Oxcarbazepine and its active metabolite MHD are effective antiepileptics in animals. They protect rodents from generalized tonic-clonic seizures and, to a lesser extent, from clonic epileptic seizures, and they suppress or reduce the frequency of chronic recurrent partial seizures in rhesus monkeys with aluminum implants. No development of tolerance (ie, reduction in anticonvulsant activity) was observed in the treatment of tonic-clonic seizures when mice and rats were treated daily for 5 days and 4 weeks, respectively, with oxcarbazepine or MHD.
Clinical Efficacy: Trileptal is used as an antiepileptic either alone or in combination with other drugs, and can replace other antiepileptic drugs if the latter provide inadequate control of seizures.
Pharmacokinetics: Absorption: Oxcarbazepine is rapidly absorbed from the gastrointestinal tract. At least 95% is absorbed following administration of the film-coated tablets and the oral suspension. The active substance undergoes rapid and extensive metabolism to the pharmacologically active metabolite 10,11-dihydro-10-hydroxy-carbamazepine (monohydroxy derivative, MHD).
In healthy male volunteers, the mean Cmax of MHD, following a single dose of 600 mg Trileptal film-coated tablets taken on an empty stomach was 31.5 micromol/L and the corresponding tmax was 5 hrs.
Following a single dose of 600 mg Trileptal oral suspension taken on an empty stomach, the mean Cmax was 24.9 micromol/L and the (median) tmax 6 hrs in healthy male volunteers.
During repeated administration, the suspension and tablet formulations are bioequivalent.
Food does not affect either the extent or the rate of oxcarbazepine absorption, and Trileptal may thus be taken with or without food.
Distribution: The apparent distribution volume of MHD is 49 L. About 40% of MHD is bound to serum proteins, in particular albumin. Within the relevant therapeutic range, binding was not dependent on serum concentration. Oxcarbazepine and MHD do not bind to α-1 acid glycoproteins.
Oxcarbazepine and its active metabolite (MHD) cross the placental barrier. Neonatal and maternal plasma MHD concentrations were similar in one case.
In a mass balance study in humans, unchanged oxcarbazepine accounted for only 2% of total radioactivity in the serum, while about 70% was attributable to MHD, with the rest being associated with minor metabolites that were quickly eliminated.
MHD reaches steady state serum concentrations within 2-3 days in patients given Trileptal twice daily. The pharmacokinetics of MHD at steady state are linear and there is a linear relationship between levels of MHD and dosage at daily doses of 300-2400 mg.
Metabolism: Cytosolic enzymes in the liver rapidly convert oxcarbazepine to MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is further metabolized by conjugation with glucuronic acid. Small amounts (4% of the dose) are oxidized to the pharmacologically inactive metabolite 10,11-dihydroxy derivative (DHD).
Elimination: Oxcarbazepine is primarily excreted via the kidney, principally in the form of metabolites. More than 95% of the dose is present in the urine, with <1% as unchanged oxcarbazepine. Less than 4% of the administered dose is excreted in the faeces. About 80% of the dose is excreted in the urine either as MHD glucuronide (49%) or as unchanged MHD (27%); inactive DHD represents about 3% of the dose and the conjugate of oxcarbazepine about 13%.
Oxcarbazepine is rapidly eliminated from the serum with a half-life between 1.3-2.3 hrs. In contrast, the mean serum half-life of MHD is 9.3±1.8 hrs.
Special Populations: Elderly Patients: Following administration of single (300 mg) and multiple (600 mg/day) doses of Trileptal, maximum serum concentrations and AUC values of MHD were 30-60% higher in older (60-82 years) than in younger (18-32 years) volunteers.
Comparisons of creatinine clearance in younger and older volunteers indicate that the difference was caused by age-related reduction of creatinine clearance. No special dose recommendations are necessary in patients with normal renal function since therapeutic doses are individually titrated (see Dosage & Administration).
Children: Weight-adjusted MHD clearance decreases as age and weight increase and gradually approaches that of adults. Mean weight-adjusted clearance in children 1 month to <4 years is 93% higher than in adults. Therefore, MHD exposure in these children is expected to be about half that of adults when treated with a similar weight-adjusted dose. Mean weight-adjusted clearance in children 4-12 years is 43% higher than in adults. MHD exposure in these children is therefore expected to be about 2/3 that of adults when treated with a similar weight-adjusted dose.
As weight increases, for patients ≥13 years, weight-adjusted MHD clearance is expected to reach that of adults.
Sex: No sex-specific differences were observed in children, adults or elderly patients.
Impaired Hepatic Function: The pharmacokinetics and metabolism of oxcarbazepine and MHD were investigated following administration of single oral doses of 900 mg in healthy volunteers and patients with impaired liver function. A slight to moderate impairment of liver function had no effect on the pharmacokinetics of oxcarbazepine or MHD. Trileptal has not been studied in patients with severe hepatic impairment.
Impaired Renal Function:
There is a linear correlation between creatinine clearance and renal clearance of MHD. Following oral administration of single 300 mg doses of Trileptal in patients with renal impairment (creatinine clearance <30 mL/min), the elimination half-life of MHD is extended by 60-90% (16-19 hrs), with a corresponding doubling of AUC.
Toxicology: Preclinical Data: Preclinical data indicate no special hazard for humans based on repeated-dose toxicity, safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite monohydroxy derivate (MHD).
Evidence of nephrotoxicity was noted in repeated-dose toxicity rat studies but not in dog or mouse studies. As there are no reports of such changes in patients, the clinical relevance of this finding in rats remains unknown.
Immunostimulatory tests in mice showed that MHD (and to a lesser extent, oxcarbazepine) can induce a delayed hypersensitivity reaction.
Reproductive Toxicity: Animal studies revealed effects eg, increases in the incidence of embryo mortality and some delay in antenatal and/or postnatal growth at maternally toxic dose levels. In 1 of the 8 embryotoxicity studies conducted with either oxcarbazepine or the pharmacologically active metabolite (MHD), there was an increase in rat fetal malformations at a dose which also showed maternal toxicity (see Use in pregnancy & lactation under Precautions).
Carcinogenicity: In carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes, an inductive effect which, although it cannot be entirely excluded, is weak or absent in patients treated with Trileptal. Testicular tumours may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable to the anticipated clinical exposure. The mechanism for the development of these tumours has not been elucidated. Thus, the clinical relevance of these findings is not known.
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