The Clinical Pharmacology of Carbamazepine

In controlled clinical trials, Carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine (CAS NO: 298-46-4) greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of Carbamazepine, Carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Carbamazepine has not been established.

Pharmacokinetics

In clinical studies, Carbamazepine suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the extended-release tablet slightly slower, than the conventional tablet. The bioavailability of the extended-release tablet was 89% compared to suspension.

Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Carbamazepine suspension affords steady-state plasma levels comparable to Carbamazepine tablets given b.i.d. when administered at the same total mg daily dose.

Following a b.i.d. dosage regimen, Carbamazepine extended-release tablets afford steady-state plasma levels comparable to conventional Carbamazepine tablets given q.i.d., when administered at the same total mg daily dose. Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of Carbamazepine are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of Carbamazepine and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions).

Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional Carbamazepine tablets, and 3 to 12 hours after administration of Carbamazepine extended-release tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Carbamazepine in serum. Because Carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses.

Carbamazepine is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of Carbamazepine-10,11-epoxide from Carbamazepine. After oral administration of 14C-Carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Carbamazepine.

The pharmacokinetic parameters of Carbamazepine disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of Carbamazepine and Carbamazepine dose in children. Carbamazepine is more rapidly metabolized to Carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to Carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age).

The effects of race and gender on Carbamazepine pharmacokinetics have not been systematically evaluated.

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