Trileptal Mechanism of Action





Full Prescribing Info
Pharmacotherapeutic group: Antiepileptics. ATC code: N03A F02.
Pharmacology: Mechanism of action: The pharmacological activity of Trileptal (oxcarbazepine) is primarily exerted through the metabolite (MHD) of oxcarbazepine (see Pharmacology: PHARMACOKINETICS: Biotransformation/Metabolism as follows). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on blockade of voltage-sensitive sodium channels, thus resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminishment of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitter or modulator receptor sites were found.
Pharmacodynamics: Oxcarbazepine and its active metabolite (MHD), are potent and efficacious anticonvulsants in animals. They protected rodents against generalized tonic-clonic and, to a lesser degree, clonic seizures, and abolished or reduced the frequency of chronically recurring partial seizures in Rhesus monkeys with aluminum implants. No tolerance (i.e. attenuation of anticonvulsive activity) against tonic-clonic seizures was observed when mice and rats were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.
Clinical Studies: A total of 10 double blind, well controlled trials, 2 in adjunctive therapy and 8 in monotherapy were conducted in patients with partial seizures which included the seizure subtypes of simple, complex and partial seizures evolving to secondarily generalized seizures. All comparative trials also included patients with generalized tonic-clonic seizures.
Two dose-control monotherapy substitution trials in which patients received a variety of concomitant antiepileptic drugs which included carbamazepine, gabapentin, lamotrigine, phenytoin, and valproate confirm efficacy when these antiepileptic drugs were substituted by Trileptal. Two trials were conducted in children (aged 3 to 17 years), one in adjunctive therapy versus placebo, the other a monotherapy comparison with phenytoin.
Efficacy was demonstrated with doses ranging from 600 mg/day to 2,400 mg/day in all the primary efficacy parameters which included mean or percentage change in seizure frequency from baseline in the adjunctive trials and time to meeting pre-defined exit criteria or the percentage of patients meeting exit criteria in the monotherapy trials. It has been shown that Trileptal has similar efficacy to other first line antiepileptic drugs (i.e. valproic acid, phenytoin and carbamazepine) with a statistically significantly better tolerability profile than phenytoin as judged by withdrawals due to adverse events and, a statistically significant longer retention rate (i.e. proportion of patients who stayed on treatment). Similar proportions of patients with partial and generalized tonic-clonic seizures, who were treated with Trileptal, were seizure free over the 12 month treatment period of these trials.
Pharmacokinetics: Absorption: Following oral administration of Trileptal tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active metabolite (10-monohydroxy derivative, MHD).
After single dose administration of 600 mg Trileptal tablets to healthy male volunteers under fasted conditions, the mean Cmax value of MHD was 34 micromol/L, with a corresponding median tmax of 4.5 hours.
In a mass balance study in man, only 2 % of total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70 % was due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly eliminated.
Food has no effect on the rate and extent of absorption of oxcarbazepine, therefore, Trileptal can be taken with or without food (see DOSAGE & ADMINISTRATION).
Distribution: The apparent volume of distribution of MHD is 49 liters.
Approximately 40 % of MHD, is bound to serum proteins, predominately to albumin. Binding was independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Biotransformation/Metabolism: Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4 % of the dose) are oxidized to the pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHD).
Elimination: Oxcarbazepine is cleared from the body mostly in the form of metabolites, which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%), whereas the inactive DHD accounts for approximately 3% and conjugates of oxcarbazepine account for 13% of the dose.
Oxcarbazepine is rapidly eliminated from the plasma with apparent half-life values between 1.3 and 2.3 hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 h.
Linearity/non-linearity: Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when Trileptal is given twice a day. At steady-state, the pharmacokinetics of MHD are linear and show dose proportionality across the dose range of 300 to 2,400 mg/day.
Special populations: Hepatic impairment: The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically impaired subjects after a single 900 mg oral dose. Mild to moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. Trileptal has not been studied in patients with severe hepatic impairment.
Renal impairment: There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Trileptal is administered as a single 300 mg dose, in renally impaired patients (creatinine clearance < 30 mL/min), the elimination half-life of MHD is prolonged by up to 19 hours, with a two fold increase in AUC.
Pediatrics: After a single dose administration of 5 or 15 mg/kg of Trileptal, the dose-adjusted AUC values of MHD were 30 % lower in children aged 2-5 years than in older children aged 6-12 years. In general, in children with normal renal function, renal clearance of MHD normalised for bodyweight is higher than in adults. In children, 10 to 50 % reduction of MHD elimination half-life (5 to 9 hours) was observed compared to adults (10 hours).
Pregnancy: Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy (see DOSAGE & ADMINISTRATION and USE IN PREGNANCY & LACTATION).
Geriatric patients (65 years or above): Following administration of single (300 mg) and multiple doses (600 mg/day) of Trileptal in elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30 to 60 % higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted.
Gender: No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.
Toxicology: Non-Clinical Safety Data: Preclinical data indicated no special hazard for humans based on repeated dose toxicity, safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite, monohydroxy derivative (MHD).
Immunotoxicity: Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.
Mutagenicity: Oxcarbazepine increased mutation frequencies in one Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Oxcarbazepine and MHD produced increases in chromosomal aberrations and/or polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.
Carcinogenicity: In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumors were induced in treated animals. The occurrence of liver tumors was most likely a consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with Trileptal. Testicular tumors may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumors are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumors of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable with the anticipated clinical exposure. The mechanism for the development of these tumuors has not been fully elucidated but could be related to increased estradiol levels specific to the rat. The clinical relevance of these tumors is unclear.
Reproductive toxicity: For reproductive toxicity, see USE IN PREGNANCY & LACTATION.
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