Clinical Pharmacology and Pharmacokinetics of Oxcarbazepine

Abstract

Oxcarbazepine (OCBZ) is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ) but differing in several important aspects, notably metabolism and induction of metabolic pathways. Consequently, OXCB has fewer drug-drug interactions compared with CBZ. Absorption of OCBZ is rapid and complete. In animals it is responsible for the pharmacological effect. In humans, however, the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect. Exposure to the MHD increases dose proportionally, and steady state is achieved after only three or four doses in a twice-daily regimen. When given with food, systemic exposure to MHD increases by about 17%. MHD is eliminated with a half-life of about 8-10 h. About 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. Results suggest that the kinetics of OCBZ should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD; the glucuronide conjugate will, however, accumulate in these patients. The conversion of OCBZ to MHD is catalyzed by reductase enzymes, which are not subject to induction. Furthermore, OCBZ itself does not appear to induce the cytochrome P-450 family in general, although it does induce the P-450 IIIA subfamily, which is responsible for the metabolism of estrogens and the dihydropyridine calcium-channel blockers (e.g., nifedipine, felodipine). In patients, linear and dose-proportional kinetics with no autoinduction of metabolism simplify OCBZ dosage adjustment.

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

“…To allow sufficient time to observe enzyme induction at a clinically relevant scale, a 10-day cotherapy period based on the terminal half-life of lamotrigine (approximately 25 h after repeated doses) (Lamictal s , 2004), oxcarbazepine and MHD (approximately 2 and 9 h, respectively) (Lloyd et al, 1994) and an estimation of the necessary induction time was used. Of these 10 days, four were oxcarbazepine dose escalation days resulting in 6 days of cotherapy at maximum doses.…”

“…Two reports indicate that induction of glucuronidation pathways by oxcarbazepine may affect the metabolism of lamotrigine (May et al, 1999;Kramer et al, 2003) and another describes higher MHD concentrations in the presence of lamotrigine compared to oxcarbazepine monotherapy (Guenault et al, 2003). Drug interactions may also be theoretically possible due to the potential inhibition of glucuronidation, which is the first-step of the metabolism and excretion pathway of the active metabolite of oxcarbazepine 10-monohydroxy (MHD) (May et al, 2003) as well as the most important metabolic transformation inactivating lamotrigine (Cohen et al, 1987;Lloyd et al, 1994).…”

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…Oxcarbazepine is rapidly and completely absorbed [38] and metabolized via 10-keto reduction to its monohydroxy derivative 10-hydroxycarbazepine. 10-Hydroxycarbazepine has equal potency to oxcarbazepine in antiseizure activity, but accumulates to higher concentrations in serum [122]. 10-Hydroxycarbazepine also distributes into saliva, with salivary 10-hydroxycarbazepine concentrations ranging from 0.3 to 1.7 that of serum concentrations [9].…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…Oxcarbazepine is rapidly and completely absorbed and metabolized to its monohydroxy derivative 10-hydroxycarbazepine (Larkin et al, 1991;Lloyd et al, 1994;May et al, 2003). 10-Hydroxycarbazepine is further metabolized, primarily by glucuronidation.…”

“…10-Hydroxycarbazepine and oxcarbazepine have similar potencies for anticonvulsant activity; however, 10-hydroxycarbazepine generally accumulates to higher concentrations in serum and thus accounts for the majority of the antiseizure activity (Lloyd et al, 1994). Consequently, TDM for oxcarbazepine generally focuses on measurement of serum/plasma concentrations of the monohydroxy metabolite (Patsalos et al, 2008).…”