Oxcarbazepine

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine- 5-carboxamide) is an antiepileptic drug. Oxcarbazepine and its pharmacologically active metabolite, 10-monohydroxy derivative (MHD; 10,11-dihydro-10-hydro-carbamazepine; GP 47779) show potent antiepileptic activity in animal models comparable to that of carbamazepine (Tegretol®) and phenytoin. Oxcarbazepine and MHD have been shown to exert antiepileptic activity by blockade of voltage-dependent sodium channels in the brain.

The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine. The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in the stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and dimunition of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conduction and modulation of high-voltage activated calcium channels may contribute to the anticonvulsive effects of the drug. Oxcarbazepine is oxidatively metabolised by the liver to produce pharmacologically active 10-hydroxycarbamazepine. The clearance of oxcarbazepine is extremely rapid and insignificant quantities appear in blood, however, the metabolite is cleared more slowly and accumulates to exert the anticonvulsant effect. Measuring serum/plasma 10-hydroxycarbamazepine is an aid to the individualisation of treatment with oxcarbazepine particularly as large inter-subject variability exists between the dose of parent drug and plasma concentration of metabolite. The relationship between serum level of 10-hydroxycarbamazepine and seizure control/toxic signs continues to be investigated, however, therapeutic drug monitoring is useful when non-compliance or toxicity is suspected, particularly since the toxic signs of oxcarbazepine are similar to those of other anticonvulsant drugs.

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is responsible for the pharmacological effect of the drug. This step is mediated by cytosolic arylketone reductases. MHD is eliminated by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidised to the pharmacologically inactive dihydroxy derivative (DHD). The absorption of oxcarbazepine is complete. In plasma after a single oral administration of oxcarbazepine the mean apparent elimination half-life (t½) of MHD in adults was 8–9h. Food has no effect on the bioavailability of the highest strength of the final market image tablet (600mg). At steady state MHD displays predictable linear pharmacokinetics at doses ranging from 300 to 2400mg. In children with normal renal function, renal clearance of MHD is higher than in adults, with a corresponding reduction in the terminal t½ of MHD. Consequently, although no special dose recommendation is needed, an increase in the dose of oxcarbazepine may be necessary to achieve similar plasma levels to those in adults. In patients with moderate to severe renal impairment (creatinine clearance <30 mL/min), the elimination t½ of MHD is prolonged with a corresponding 2-fold increase in area under the concentration-time curve. Therefore, a dose reduction of at least 50% and a prolongation of the titration period is necessary in these patients. Mild-to-moderate hepatic impairment does not affect the pharmacokinetics of MHD. Based on in vitro and in vivo findings and compared with antiepileptic drugs such as carbamazepine, phenytoin and phenobarbital, oxcarbazepine has a low propensity for drug-drug interactions. In vitro, MHD inhibits the cytochrome P450 (CYP) 2C19 (ki [inhibition constant] = 88 µmol/L). At oxcarbazepine doses above 1.2g, a 40% increase in the concentration of phenytoin and a 15% increase in phenobarbital levels were observed. Oxcarbazepine/MHD at high doses may slightly increase phenobarbital and phenytoin plasma concentrations. Therefore, when using high doses of oxcarbazepine an adjustment in the dose of phenytoin may be required. In vitro, MHD is only a weak inducer of uridine diphospate (UDP)-glucuronyltransferase (UDPGT) and therefore is unlikely to have an effect on drugs that are mainly eliminated by conjugation through the UDPGT enzymes (e.g. valproic acid and lamotrigine). Weak interactions between MHD and antiepileptic drugs that are strong inducers of CYP enzymes have been identified. Carbamazepine, phenobarbital and phenytoin have been shown to reduce MHD levels by 30–40% when coadministered with oxcarbazepine, with no decrease in efficacy. Oxcarbazepine decreases the plasma hormone levels (ethinylestradiol and levonorgestrel) of oral contraceptives and may therefore have the potential to cause oral contraception failure.