Carbamazepine-10,11-epoxide in epilepsy. A pilot study

The effects of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, were evaluated in seven outpatients with frequent epileptic seizures. The study included an initial 4-week period with the carbamazepine dose optimized for each patient. Patients were then crossed over, dose by dose, to carbamazepine-10,11-epoxide and followed up for another 4 weeks. Dosing was single blind. The evaluation of the anticonvulsant effect was hampered by marked fluctuations in plasma levels during treatment with carbamazepine-10,11-epoxide. There was, however, no significant change in seizure control. During epoxide treatment, no subjective side effects were reported despite epoxide plasma concentrations up to 57 mumol/L. Neuropsychological assessment revealed a significant improvement in finger motor speed and logical reasoning during the carbamazepine-10,11-epoxide period. Subnormal serum sodium levels in two patients were normalized after switching from carbamazepine to the epoxide. Continued investigations with this active metabolite of carbamazepine in epilepsy are therefore justified.     

Total and free serum concentrations of carbamazepine and carbamazepine-10,11-epoxide in children with epilepsy

Simultaneous steady-state serum total and free (non-protein-bound) concentrations of carbamazepine and carbamazepine-10,11-epoxide were measured in 68 patients under the age of 21 years with epilepsy (44 males, 24 females; mean age, 11.8 +/- 4.5 years). Thirty patients were maintained on monotherapy with carbamazepine. Mean serum total carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 7.0 +/- 2.4 mg/L (29.5 +/- 10.0 mumol/L) and 1.5 +/- 0.6 mg/L (5.9 +/- 2.6 mumol/L), respectively. Mean serum-free carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 1.3 +/- 0.5 mg/L (5.7 +/- 2.1 mumol/L) and 0.5 +/- 0.3 mg/L (2.2 +/- 1.1 mumol/L), respectively. Binding of carbamazepine and carbamazepine-10,11-epoxide was 81% +/- 3% and 62% +/- 10%, respectively. There was no significant difference in binding between male and female patients or those maintained on monotherapy and polytherapy. Age correlated significantly with carbamazepine binding but not with carbamazepine-10,11-epoxide binding. Free concentrations of carbamazepine and carbamazepine-10,11-epoxide correlated significantly with total carbamazepine and total carbamazepine-10,11-epoxide concentrations, respectively, indicating that the binding capacities of both carbamazepine and carbamazepine-10,11-epoxide are constant at serum total carbamazepine concentrations within the quoted therapeutic range.     

Carbamazepine-viloxazine interaction in patients with epilepsy.

In six depressed epileptic patients stabilised on carbamazepine therapy, addition of the antidepressant agent viloxazine (300 mg/day for three weeks) induced a marked (average 55%) increase in steady-state plasma carbamazepine concentration. The concentration of the active metabolite carbamazepine-10,11-epoxide also increased during viloxazine therapy, but to a lesser extent (16%). In three patients, these effects were associated with symptoms of carbamazepine intoxication, which regressed rapidly when plasma carbamazepine and carbamazepine-10,11-epoxide levels returned to baseline values after discontinuation of viloxazine. In a seventh patient, viloxazine had to be discontinued after only two weeks because of severe side effects associated with a striking elevation of carbamazepine and carbamazepine 10,11-epoxide levels (by 197% and 137% respectively). Although viloxazine appears to be one of the few antidepressants which can be used safely in patients with epilepsy these results indicate that the drug should be prescribed with great caution in subjects treated with carbamazepine. The mechanism of the interaction probably involves inhibition of the metabolism of both carbamazepine and its active epoxide metabolite.     

Lack of interaction between cimetidine and carbamazepine

In order to investigate a possible interaction between cimetidine and carbamazepine (CBZ) 7 otherwise healthy epileptic patients on a long-term monotherapy with CBZ were given cimetidine (1 g daily) for 7 days. No significant alterations in steady-state plasma concentration of CBZ and the 10,11-epoxide metabolite (CBZ-E) were demonstrated.     

Prevalence of cardiac conduction disturbances during carbamazepine treatment: preliminary data

Twenty-five epileptic patients chronically treated with carbamazepine underwent 24 h electrocardiogram (ECG) monitoring in order to evaluate the prevalence of cardiac conduction abnormalities. Plasma levels of carbamazepine and its metabolite, carbamazepine-10,11-epoxide, were determined by liquid chromatography. Six patients had mild ECG abnormalities. These patients did not differ from the others with respect to plasma concentrations of the drug and its metabolite.     

EEG changes in patients during the introduction of carbamazepine.

This study evaluates the EEG changes during the standardized introduction of carbamazepine in 16 previously untreated neurological patients and their relationship to serum levels of carbamazepine and carbamazepine-10,11-epoxide. Therapy was started with a dosage of 400 mg carbamazepine b.i.d. and remained unchanged during the whole study period of 35 days. Frequency analysis of serial EEG records was performed by Fast Fourier Transformation. In comparison to the pretreatment period (1) the mean values of the total power and relative powers of the theta and delta bands increased and (2) the mean values of the relative power of the alpha band and the center frequency decreased. These changes were already established 3 days after the beginning of the treatment and remained constant during the observation period. There were marked interindividual differences. (3) There was no statistically significant correlation between serum levels of carbamazepine or carbamazepine-10,11-epoxide and the EEG parameters. Our results demonstrate that the degree of EEG change primarily reflects individual susceptibility to carbamazepine and its metabolite during the early stage of carbamazepine exposure and is not dose related.     

EEG changes in patients during the introduction of carbamazepine

This study evaluates the EEG changes during the standardized introduction of carbamazepine in 16 previously untreated neurological patients and their relationship to serum levels of carbamazepine and carbamazepine-10,11-epoxide. Therapy was started with a dosage of 400 mg carbamazepine b.i.d. and remained unchanged during the whole study period of 35 days. Frequency analysis of serial EEG records was performed by Fast Fourier Transformation. In comparison to the pretreatment period (1) the mean values of the total power and relative powers of the theta and delta bands increased and (2) the mean values of the relative power of the alpha band and the center frequency decreased. These changes were already established 3 days after the beginning of the treatment and remained constant during the observation period. There were marked interindividual differences. (3) There was no statistically significant correlation between serum levels of carbamazepine or carbamazepine-10,11-epoxide and the EEG parameters. Our results demonstrate that the degree of EEG change primarily reflects individual susceptibility to carbamazepine and its metabolite during the early stage of carbamazepine exposure and is not dose related.     

Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine)

A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.     

Carbamazepine-induced thrombocytopenia and carbamazepine-10,11-epoxide: A case report

Abstract The case of a patient who developed thrombocytopenia during treatment with carbamazepine (CBZ) is described. The platelet count recovered soon after discontinuation of CBZ. Lymphocyte stimulation test with carbamazepine-10,11-epoxide (CBZ-10,11-EPOX), a major metabolite of CBZ, was positive, although with CBZ it was negative. These findings suggest that CBZ-10,11-EPOX was possibly causative in the pathogenesis of CBZ-induced thrombocytopenia in this case.     

Disposition of Carbamazepine and Phenytoin in Pregnancy

Summary: Free and total plasma concentrations of phenytoin (PHT) and carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZ-E) were determined in a prospective study of 86 pregnant epileptic women. The pharmacokinetics of PHT and CBZ during the three trimesters were compared with kinetics at least 10 weeks postpartum. Plasma clearance and unbound CBZ clearance were slightly decreased during the last trimester. Total and free plasma CBZ-E concentrations did not change significantly during pregnancy. Plasma PHT clearance, on the other hand, increased from the first trimester. A less pronounced increase was observed for clearance of unbound PHT; the increase was statistically significant only during the third trimester.     

Carbamazepine Dose Requirements During Stiripentol Therapy: Influence of Cytochrome P-450 Inhibition Stiripentol

The inhibitory effect of stiripentol (STP) on disposition of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZE) was quantitated to establish CBZ dosage reduction guidelines for future clinical add-on efficacy trials of STP. In seven epileptic patients, STP (1,500-3,000 mg/day for 2 weeks) inhibited CBZ clearance by 50 +/- 16% (p = 0.001) and reduced the CBZE/CBZ plasma ratio by 45 +/- 14% (p = 0.0005). The inhibitory effect was gradually manifested over a period of 7-10 days after initiation of STP therapy. In contrast to inhibition of CBZE formation, STP had no effect (p greater than 0.05) on elimination clearance or half-life (t1/2) of CBZE in six healthy volunteers. STP most likely exerts inhibitory effects through inhibition of cytochrome P-450. This hypothesis was confirmed in the present study by the finding that a therapeutic concentration of STP (7 micrograms/mL) inhibited 10,11-epoxidation of CBZ in human liver microsomes by 40-50%. On the basis of results from this study, we propose that (a) CBZ dosage should be reduced in steps over a period of 7-10 days after initiation of STP, and (b) a CBZ dosage of 4.3 to 8.7 mg/kg/day will maintain therapeutic CBZ plasma levels of 5-10 micrograms/mL.     

ALTERED RATIO OF CARBAMAZEPINE-10,11-EPOXIDE/CARBAMAZEPINE IN PLASMA OF CHILDREN: EVIDENCE OF ANTICONVULSANT DRUG INTERACTION

A method of measuring carbamazepine-10,11-epoxide (CBZ-10,11-EPOX) has been developed and used to monitor plasma concentrations in children suffering from various forms of epilepsy. Children stabilised on standard doses of CBZ alone showed a ratio of CBZ-10,11-EPOX/CBZ of 18.92 +/- 8.08, expressed as a percentage of the CBZ concentration, while those on multiple-drug therapy (with the exception of benzodiazepines and phenobarbitone) showed both increased values of CBZ-10,11-EPOX/CBZ ratio and increased absolute concentrations of CBZ-10,11-EPOX in plasma. These changes correlated with clinical side-effects which could not be attributed to CBZ itself or to the other drugs administered concurrently.     

A Comprehensive Study of the Relation Between Serum Concentrations, Concentration Ratios, and Level/Dose Ratios of Carbamazepine and Its Metabolites with Age, Weight, Dose, and Clearances in Epileptic Children

Summary: We made a comprehensive study of the relation between age, weight, carbamazepine (CBZ) dose, total clearance (TC), and intrinsic clearance (IC) and concentrations, concentration ratios, and level/dose ratios of CBZ, carbamazepine-10,11-epoxide (CBZ-E) and trans -10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-H) in a group of epileptic children receiving CBZ monotherapy. Body weight and age showed negative correlations with TC, IC, CBZ dose, and CBZ-E/CBZ and CBZ-HI CBZ concentration ratios, and had positive relation with CBZ, CBZ-E, and CBZ-H level/dose ratios. These results indicate decreased CBZ metabolism with patient maturity. Correlations between CBZ dose with TC, IC, and the concentration ratios of CBZ-E/CBZ, CBZ-H/CBZ-E, and CBZ-H/CBZ were positive. CBZ dose also had negative associations with CBZ and CBZ-E level/dose ratios, indicating dose-dependent autoinduction of CBZ metabolism. Our data suggest that weight, age, and CBZ dose have less influence on epoxidehydrolase activities than on epoxidase activities. The CBZ-E/CBZ concentration ratio can be used as an indicator of the degree of autoinduction of CBZ metdbohn, even in patients receiving CBZ monotherapy.     

Valproic acid-induced carbamazepine-10,11-epoxide toxicity in children and adolescents

The study of 14 children and adolescents shows that the addition of carbamazepine (CBZ) to a basic valproic acid (VPA) therapy can result in unexpectedly high concentrations of carbamazepine-10,11-epoxide (CE) in the serum (up to 13 micrograms/ml). These concentrations were associated with marked side effects, especially vomiting and tiredness. The concentrations of CBZ were within the therapeutic range. Very high CE concentrations can largely be avoided at the commencement of the CBZ treatment if the CBZ dose is slowly increased. But high CE concentrations (4-8 micrograms/ml) associated with side effects can also be reached in later stages during the build up of CBZ treatment and under steady state conditions. The determination of the CE concentration is important when VPA and CBZ are administered together, especially when side effects occur.     

The 24 hour variation of salivary carbamazepine and carbamazepine-10,11-epoxide concentrations in children with epilepsy

Variations in carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-EP) concentrations were measured in saliva over 24 hours in 33 children with complex partial seizures and/or generalized tonic-clonic seizures; all patients received CBZ as monotherapy. CBZ varied between 37–104% and CBZ-EP varied between 26–119%. One venous blood sample was obtained simultaneously with the first saliva sample before the morning dose of CBZ. The free fraction of plasma CBZ was 25.5%. Medication side effects are most likely to appear within 3–4 hours of drug intake; therefore, it is advisable to take another sample in children demonstrating time-related side effects. A controlled release formulation of CBZ should minimize the fluctuations of salivary drug levels of CBZ and CBZ-EP.     

Persistent upregulation of brain adenosine receptors in response to chronic carbamazepine treatment

Chronic carbamazepine treatment for a period of 2 weeks caused a highly significant increase in brain adenosine receptors in the rat. The carbamazepine was administered in food pellets in a diet that achieved clinically relevant total plasma concentrations of carbamazepine and its active-10,11-epoxide metabolite. Of the several brain areas examined, the cerebral cortex and hippocampus exhibited the most robust increases in [3H]cyclohexyladenosine (CHA) binding. Increases of 35-40% were observed in these brain regions whereas an 8-10% increase was seen in the cerebellum. The carbamazepine induced increase in brain adenosine receptors in all these areas persisted unabated at 1 and 5 days as well as 2, 4, and 8 weeks following termination of carbamazepine treatment, suggesting a relatively permanent alteration of the adenosine receptor by this drug.     

Multiple-dose pharmacokinetic study with a slow-release carbamazepine preparation

The pharmacokinetics, clinical efficacy and side effects of carbamazepine (CBZ) in the steady-state condition were studied using a slow-release preparation (SR), Neurotol Slow, and a conventional preparation (C), Tegretol. Eighteen adult epileptic patients under CBZ therapy were evaluated in this single-blind, randomized cross-over study. The previous daily CBZ dose was kept unchanged and divided into 2 daily doses during two 2 week study periods. At the end of each period blood samples were drawn at frequent intervals for 12 h after the administration of the morning CBZ dose. Serum concentrations of unchanged CBZ and its main metabolite, carbamazepine-10,11-epoxide (CBZE), were determined by HPLC. Peak concentrations of CBZ and CBZE were significantly lower, and the time-lapse before CBZ reached its peak was significantly longer during SR treatment. The fluctuations in serum CBZ and CBZE were significantly lower during SR treatment. There was no significant difference in bioavailability between the 2 preparations. The number of epileptic seizures was 31 during SR and 57 during C treatment. Side effects were more common during C treatment. The occurrence of dizziness was significantly lower with SR treatment than with C treatment. We conclude that greater stability in serum CBZ and CBZE concentrations can be obtained by using an SR of CBZ, without reducing the bioavailability of the drug.     

Influence of Additional Therapy with Zonisamide (Excegran) on Protein Binding and Metabolism of Carbamazepine

Summary: The influence of comedication with zonisamide (ZNS) on protein binding and carbamazepine (CBZ) metabolism was studied in 16 pediatric epileptic patients. Correlations were evaluated between ZNS daily dose and individual change of level per dose ratio (L/D ratio), free fraction, and carbamazepine-10,11-epoxide/CBZ level ratio (CBZEKBZ). Statistical significant negative correlation was observed between LID ratio and ZNS daily dose. Despite alteration in the L/D ratio, the free fraction of CBZ was unaltered in combination with ZNS. To assess the effect of addition of ZNS on CBZ metabolism, the CBZE/CBZ level ratio was compared; this ratio showed a tendency to increase with increase in ZNS dose. Consequently, ZNS is considered to have a significant effect on CBZ metabolism but not on protein binding.     

Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide.

We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamazepine (CBZ) and its primary metabolite CBZ-10,11-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P less than 0.01) and the CBZ-E/CBZ ratio increased by 19% (P less than 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.     

Pharmacokinetics and drug interactions of eslicarbazepine acetate

Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t(1/2,eff) ) of eslicarbazepine was 20-24 h, which is approximately two times longer than its terminal half-life (t(1/2)). At clinically relevant doses (400-1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin.