Oxcarbazepine

Ahmad Beydoun

Wassim M. Nasreddine

Fiorenzo Albani

Introduction

Although oxcarbazepine (OXC) has been available for many years in Europe, it was only approved by the Food and Drug Administration (FDA) for use in the United States in early 2000. Since its launch its use for partial epilepsy has increased, and it is currently considered by experts as a first-line medication for all partial-onset seizures.³²

Chemical Structure and Methods for Determination in Body Fluids

OXC (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carb-oxamide; Trileptal, Timox, Tolep) is a derivative of carbamazepine, from which it differs by a ketone group at position 10. OXC is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether, and water. Its molecular weight is 252.3. Its main metabolite, mono-10-hydroxy derivative (MHD), is a neutral lipophilic compound with a molecular weight of 254.3. Chemically, MHD is a racemic compound composed of R(–) and S(+)-MHD.

OXC and MHD levels can be determined in biologic matrices by high-performance liquid chromatography (HPLC) and gas chromatography.²³^,³⁶ HPLC is the most common procedure, and specialized methods continue to be developed for use in routine therapeutic drug monitoring,¹⁹ in pharmacokinetic studies requiring the analysis of metabolites,¹³ and in the separation of the MHD enantiomers.⁵⁸ Currently, no immunoassays for the determination of OXC or MHD are commercially available.

Pharmacology and Mechanisms of Action

In animal models, OXC and MHD are active against tonic extension seizures induced by maximal electroshock and against focal seizures in monkeys with chronic aluminum foci; they have little or no activity against clonic seizures induced by phenothiazine, picrotoxin, and strychnine. This anticonvulsant profile is similar to that of carbamazepine.⁶⁰ The main mechanism of action of OXC and MHD is assumed to be the use-dependent inactivation of voltage-gated brain sodium channels.³⁸^,⁵¹ Limited experimental data suggest that some of their anticonvulsant effects are mediated through action at the potassium channels and at the high-threshold, voltage-gated type N- and/or P- and/or R-type Ca²⁺ channels,³⁸^,⁵¹^,⁶⁰ actions that may differentiate OXC from carbamazepine.⁴⁹

Clinical Pharmacokinetics

The clinical pharmacokinetics of OXC have been recently reviewed.²³^,³⁶ Plasma concentrations of OXC in chronically treated patients are very low with respect to MHD, and MHD is assumed to be the clinically relevant compound. Most pharmacokinetic and disposition studies focus on the racemic MHD, and only limited data are available for the separate enantiomers.

Absorption

After oral administration OXC is rapidly absorbed from the gastrointestinal tract, with a bioavailability >90%; peak concentration (C_max) of OXC and MHD occurs within 1 to 3 hours and 4 to 6 hours, respectively.²³^,³⁶

The effect of food on the pharmacokinetics of OXC, at least with the currently marketed pharmaceutical preparation, is minimal, and without therapeutic relevance.²³^,³⁶

Plasma Protein Binding and Distribution

The reported apparent volume of distribution (V_d) of MHD ranges from 0.3 L/kg (estimated from urine data) to 0.7 to 0.8 L/kg.³⁶

Approximately 40% of the total MHD is bound to plasma proteins, mainly albumin. Data are consistent for healthy volunteers and patients with different pathologies. The binding seems to be independent of serum concentration within the therapeutically relevant range. Protein binding of OXC is slightly higher, at about 60%.³⁶

The erythrocytes/plasma concentration ratio in various studies ranged from 0.88 to 1.34,³¹ to 0.9 to 1.75,²⁷ to 1.4 to 1.9,⁵⁵ suggesting some accumulation in erythrocytes.

Published data on brain and cerebrospinal fluid (CSF) concentrations of MHD and OXC are scanty. May et al.,³⁶ citing their own unpublished data and data on three patients reported by Christensen et al.,¹⁷ indicated that MHD CSF concentrations are 50% to 60% of total plasma concentrations. Similarly, citing their own unpublished data in 13 patients undergoing surgery for epilepsy, May et al.³⁶ reported slightly lower (by about 14 ± 6%) MHD concentrations in the neocortex as compared to serum. In a recent paper, Marchi et al.³⁵ studied nine patients undergoing brain surgery for epilepsy and found that brain and plasma concentrations of MHD did not correlate (brain-to-plasma ratio ranging from 1% to 103%), whereas in eight patients, the MHD brain-to-plasma ratios were correlated to the level of expression of the multidrug transporter MDR1 mRNA, measured in resected epileptic hippocampal or cortical tissues. The same paper showed that MHD is also a substrate for the multidrug transporter protein P-gp. Clinckers et al.¹⁸ indicated that OXC is a substrate for multidrug transporters at the blood–brain barrier.

OXC and MHD can be transferred significantly through the placenta in humans, with comparable concentration in the maternal and umbilical cord serum. Concentrations of OXC and MHD in breast milk are about 50% of the corresponding plasma concentrations.²³^,³⁶

Metabolism

After administration, OXC undergoes presystemic metabolic 10-keto reduction to MHD mediated by cytosol arylketone reductases. MHD is then cleared by uridine diphosphate glucuronyl-transferase (UGT)-mediated glucuronide conjugation and, to a lesser extent, by cytochrome P450 (CYP)-mediated oxidation to 10,11-trans-di-hydroxy metabolite (dihydroxy derivative [DHD]), an inactive metabolite also derived from carbamazepine.

The reduction of OXC to MHD is stereoselective, with the formation of (S)-(+)-MHD and (R)-(–)-MHD. After oral administration of OXC to healthy volunteers, the plasma concentration-time curves (AUC) of the (S)- and (R)-enantiomers were in the ratio of about 4:1.¹⁰^,²³^,³⁶ As the two enantiomers seem to have similar anticonvulsant properties,⁵¹ this pharmacokinetic imbalance probably lacks clinical relevance.

Elimination

OXC exhibits first-order linear kinetics during long-term administration. MHD plasma concentrations vary linearly with the OXC dose within patients, although marked interindividual variability was observed.

Elimination half-lives of 1 to 5 hours for OXC and of 7 to 20 hours (mean values) for racemic MHD were reported in studies of healthy volunteers after single or repeated doses of OXC. The half-life can be shorter in pediatric patients and in patients treated with enzyme-inducing antiepileptic drugs (AEDs).³⁶

After single-dose administration in healthy volunteers, some authors described a monoexponential decay of MHD, whereas others observed a biphasic MHD concentration-time curve, suggesting that the metabolism of OXC is a saturable process, and that enterohepatic recirculation of OXC might occur. The possibility that OXC reduction is a saturable process at higher dosages is also suggested by a clinical case of attempted suicide with a large dose of OXC (about 30 g), where higher ratios of OXC to MHD concentrations were found.⁵⁷

Reported values of renal clearance (CL_R) of MHD in healthy volunteers (young adults) ranged from 12 to 14 mL/min to about 58 mL/min.³⁶ Methodologic differences between the various studies probably contribute to the wide variability observed. Renal clearance did not differ between the (R)- and the (S)-enantiomers.¹⁰

Pharmacokinetics in Special Populations

Most available data on OXC and MHD kinetics in children are published as abstracts only. Children younger than 5 to 6 years show higher renal clearance, lower dose-normalized AUC of MHD, and a shorter MHD half-life than adults and older children.²³^,³⁶ Consequently, an increased dose in mg/kg body weight may be needed in children to achieve plasma levels similar to those of adults.

In elderly subjects aged 60 to 82 years, the dose-normalized AUC of MHD was higher than in young adults (18 to 32 years) and related to creatinine clearance, suggesting that the differences in pharmacokinetics are due to impaired MHD renal clearance with age. Consistently, a modest effect of age on MHD concentrations was observed in patients.²³^,³⁶

Bulau et al.¹⁴ reported similar plasma concentrations of OXC and MHD in a newborn girl and in the treated mother. Concentrations of both compounds in the newborn declined rapidly over days in spite of the availability of both compounds via breast milk.

Therapeutic Drug Monitoring

No clearcut relationship between plasma concentrations and clinical effects has been demonstrated for OXC or MHD. Therapeutic drug monitoring of MHD can be useful in titrating patients whose epilepsy is difficult to control and in cases of questionable compliance and drug–drug interactions, or to confirm concentration-related drug toxicity. As for many other AEDs, however, a precise optimal interval of MHD plasma concentrations has not been defined in prospective controlled studies, but derived from clinical trial data and clinical experience. The most often reported values range from 12.5 to 15.0 μg/mL to 30 to 35 μg/mL.³⁰

Efficacy

Partial-Onset Seizures

OXC is approved in the European Union and the United States for initial monotherapy, conversion to monotherapy, and adjunctive therapy in children and adults suffering from partial-onset seizures. Its efficacy was established in a number of multicenter, double-blind, randomized clinical trials in varying patient populations with localization-related epilepsy, ranging in severity from the newly diagnosed to the medically refractory patients being evaluated for epilepsy surgery.

Active-Control Comparative Monotherapy Trials in Newly Diagnosed Epilepsy

The efficacy of OXC was evaluated in four comparative, double-blind, parallel-group trials conducted in adults¹¹^,¹⁶^,²⁰ and children²⁹ with newly diagnosed epilepsy. The trial design was similar across all four trials. Patients who had experienced a minimum of two seizures in the preceding 6 months were randomized to treatment with OXC versus phenytoin,¹¹^,²⁹ valproate,¹⁶ or carbamazepine.²⁰ The trials consisted of an 8-week titration phase followed by a 48-week maintenance phase. OXC was initiated at 300 mg/day on a tid schedule (150 mg/day in the trial conducted in children and adolescents) and gradually titrated biweekly based on the clinical response during the 8-week titration phase. The primary efficacy variable was the percentage of patients who remained seizure free throughout the 48-week maintenance phase. Secondary outcome variables included the percentage of patients who exited due to adverse events and treatment retention.

There were no significant differences in the primary efficacy variable between OXC and the comparator drugs in any of the trials (Table 1). The median daily doses of OXC during the maintenance phase of the three adult trials were 1,053 mg, 1,028 mg, and 1,040 mg (mean dose). The corresponding values for phenytoin, valproate, and carbamazepine were 313 mg, 1,146 mg, and 684 mg (mean dose), respectively. For the trial conducted in children and adolescents, the median daily doses of OXC and phenytoin were 18.8 mg/kg and 5.8 mg/kg, respectively. OXC was, however, better tolerated than phenytoin or carbamazepine based on significantly lower exit rates due to adverse events (Table 1). There was no significant difference in exit rates due to adverse events between OXC and valproate.

Although those trials are frequently alleged to demonstrate equivalent efficacy of OXC to that of the standard AEDs, it is important to note that these studies were not powered as
equivalence or noninferiority trials. The controversies surrounding the interpretative difficulties of equivalency trials were recently discussed.⁷

Table 1 Active-control Comparative Trials of Oxcarbazepine in Patients with Newly Diagnosed Epilepsy

	Patients (No.)	Daily dosage (mg)	Seizure free	Exit rate	Exit rate due to AE
OXC vs. PHT (5–18 yr)²⁹	OXC (97) PHT (96) Total (193)	OXC (300–1,350) PHT (100–400)	OXC 61% PHT 60%	OXC 24% PHT 34%	OXC 2%^a PHT 14%
OXC vs. VPA (15–65 yr)¹⁶	OXC (128) VPA (121) Total (249)	OXC (600–2,400) VPA (600–2,700)	OXC 56.6% VPA 53.8%	OXC 52% VPA 41%	OXC 15% VPA 10%
OXC vs. PHT (16–65 yr)¹¹	OXC (143) PHT (144) Total (287)	OXC (600–2,100) PHT (100–650)	OXC 59.3% PHT 58.0%	OXC 56% PHT 61%	OXC 5%^a PHT 16%
OXC vs. CBZ (14–63 yr)²⁰	OXC (94) CBZ (100) Total (194)	OXC (300–1,800) CBZ (300–1,400)	OXC 52% CBZ 60%	OXC 16% CBZ 27%	OXC 14%^a CBZ 25%
AE, adverse events; CBZ, carbamazepine; OXC, oxcarbazepine; PHT, phenytoin; VPA, valproate. ^a p <0.05.