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PEDIATRICS |
From the Hôpital St. Vincent de Paul, Paris, France (Dr. Rey, Dr. Bulteau, Dr. Tran, Dr. Pons, Dr. Dulac); Hôpital Americain, Reims, France (Dr. Motte); Novartis Pharma AG, Basel, Switzerland (Dr. Sturm); and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr. D'Souza, Dr. Markabi).
Address for reprints: Elisabeth Rey, PharmD, Hôpital St. Vincent de Paul, 74, Avenue Denfert-Rochereau, 75 674 Paris Cedex 14, France.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Oxcarbazepine • pharmacokinetics • safety • tolerability • inadequately controlled epilepsy • pediatrics • antiepileptic drugs
Clinical trials in adults with partial and generalized tonic-clonic seizures have demonstrated the clinical effectiveness of oxcarbazepine relative to standard AEDs.3-7 The pharmacokinetics of oxcarbazepine and its main active metabolite have also been characterized in adults.8,9
Oxcarbazepine (450-2400 mg/day) was evaluated as monotherapy in 193 children 5 to 17 years of age with epilepsy in a double-blind comparison with phenytoin (150-800 mg/day).10 Although seizure control did not differ between the two treatment groups, oxcarbazepine was better tolerated than phenytoin. Oxcarbazepine was also evaluated as combination therapy in 267 children 3 to 17 years of age with partial seizures that were inadequately controlled with one or two concomitant AEDs.11 During the double-blind, placebo-controlled phase of this study, patients treated with oxcarbazepine (6-51 mg/kg/day, median = 31.4 mg/kg/day) experienced a significantly greater reduction in seizure frequency (P = .0001) than patients receiving placebo. Previous clinical experience also suggested that oxcarbazepine is effective and well tolerated in children 2 years of age and older.12,13 A population pharmacokinetic analysis of MHD, using data collected in the large randomized controlled study described above,11 has recently shown age-dependent pharmacokinetics in children.14 For example, the clearance of MHD was higher in younger children compared with older children and adults. The present study was conducted to further assess the safety and tolerability of oxcarbazepine in children with inadequately controlled epilepsy and to compare the pharmacokinetics of oxcarbazepine and MHD in younger children (2-5 years of age) and older children (6-12 years of age).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The study was conducted in accordance with the Declaration of Helsinki. Approval of the study protocol was obtained from the ethical committee of the Cochin, Saint-Vincent de Paul, and Saint-Anne hospitals prior to implementation. Written, informed consent was provided by a parent or legal guardian for all participating children.
Study Design
This was a two-part pharmacokinetic, safety, and tolerability study in pediatric patients 2 to 12 years of age with partial-onset and/or generalized tonic, atonic, or tonic-clonic seizures. Patients were enrolled from 12 centers in France. Part I was an open-label, single-dose, randomized, single-center pharmacokinetic study. Eligible patients were stratified into two age groups (2-5 years and 6-12 years) and randomized to receive oxcarbazepine at a dose of 5 or 15 mg/kg administered as an oral suspension. Limits for the ages of children admitted to the study were chosen according to Food and Drug Administration (FDA) and European Medicinal Evaluation Agency (EMEA) guidelines; age ranges for stratification into the two age groups were selected empirically to represent younger children (2-5 years of age) and older children (6-12 years of age). During part I, children were hospitalized, and concurrent AED treatment remained unchanged. Following administration of oxcarbazepine, blood samples (approximately 1 mL each) were collected for pharmacokinetic analyses into heparinized tubes at approximately 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours postdose. Plasma was separated and stored at -80°C until analysis. Patients from part I participated in part II.
Part II was an open-label, long-term safety, tolerability, multiple-dose pharmacokinetic study of oxcarbazepine as combination therapy in children stratified by age (2-5 years and 6-12 years). Part II consisted of two phases: a screening phase and an open-label treatment phase. Study eligibility was determined during a 28-day screening phase, in which patients were evaluated for seizure type, frequency, and severity based on physical and neurological examination, electroencephalography, and computed tomography scans and/or magnetic resonance imaging. History of AED treatment, hematology, blood chemistry, and plasma AED concentrations were also assessed during the screening phase. The open-label treatment phase consisted of three periods: a 56-day flexible titration period, a 4-month maintenance period, and a 12-month follow-up period.
Based on previous experience with both tid and bid administration in adult patients, oxcarbazepine treatment was initiated at 10 mg/kg/day administered in three divided doses. Oxcarbazepine could be administered twice daily, especially in younger children receiving "low" daily doses. Oxcarbazepine was supplied as 300-mg divisible tablets, and administration of one-half or one-quarter of a tablet was permitted to achieve optimal dosing. In younger children unable to ingest tablets, parents were allowed to crush the tablets immediately before administration. Although crushing the tablets might have had an impact on the bioavailability of the drug, individual trough levels were measured to further characterize pharmacokinetics during therapeutic conditions in steady state. The initial dosage of 10 mg/kg/day was increased to 20 mg/kg/day within the first 2 weeks of the titration period. Thereafter, the dose could be adjusted until an optimal dose was achieved that provided maximum therapeutic benefit with satisfactory tolerability, as determined by the investigator. The maximum oxcarbazepine dose allowed was 50 mg/kg/day; however, in exceptional cases, dose increases beyond the maximum dose were permitted if previously approved by the sponsor's medical monitor.
The 4-month maintenance period was designed to provide patients who experienced therapeutic benefit during the titration period with an extended period of oxcarbazepine treatment at optimal therapeutic doses. Doses of concomitant AEDs were to remain stable throughout the study. Patients returned to the clinic at 8-week intervals for evaluation of therapeutic effect and safety monitoring. The 12-month follow-up period was designed to provide continued oxcarbazepine therapy for those patients who experienced therapeutic benefit on completion of the maintenance period. Periodic safety assessments occurred twice during the 12-month follow-up period at 6-month intervals. Blood samples for the determination of trough plasma oxcarbazepine and MHD concentrations were obtained throughout the study (days 0, 14, 28, 42, 56, 120, 180, 360, and 540). The study protocol was amended to allow for continuing oxcarbazepine therapy for patients who benefited from treatment until oxcarbazepine was registered and commercially available in France.
Analytical Methods and Pharmacokinetic Variables
Plasma samples were analyzed for oxcarbazepine and MHD using high-performance liquid chromatography.15 The lower limits of quantitation for oxcarbazepine and MHD in plasma were 0.2 µmol/L and 0.4 µmol/L, respectively. During part I, the following pharmacokinetic parameters were evaluated using a noncompartmental approach with no assumptions: maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), time to maximum plasma concentration (tmax) for both oxcarbazepine and MHD, and half-life (t1/2) and mean residence time (MRT) for MHD only.
MRT for MHD was calculated as follows:
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where AUMC(0-t) is the area under the first moment curve calculated by the trapezoidal rule up to time t.
These parameters were compared for the 5- and 15-mg/kg oxcarbazepine dose levels and the two age groups. Values of Cmax and AUC were adjusted for dose administered by body weight (specific values). During part II of the study, trough plasma oxcarbazepine and MHD concentrations were obtained and evaluated in relation to dose. All data analysis was performed using SAS software.
Safety and Tolerability Variables
The primary safety and tolerability variables were based on the AEs reported during the study. The nature of the AEs was recorded, in addition to the date of onset, end date, severity, relation to trial treatment, action(s) taken, and the outcome of any sign or symptom observed by the physician or reported by the patient. This information was obtained by questioning and/or examining the patient. Serious AEs were reported immediately, and appropriate follow-up action was taken. Secondary variables were electroencephalography, physical examinations (vital signs and weight), clinical laboratory evaluations, and plasma concentrations of concomitant AEDs.
Efficacy Variables
Although efficacy was not a primary objective of this study, seizure frequency and seizure type were recorded during the 28-day screening phase and throughout the study.
Statistical Analyses
For part I, analysis of variance (ANOVA) was applied to the log-transformed pharmacokinetic parameters of MHD: Cmax and AUC(0-
) for specific values (concentration/dose), t1/2, and MRT. Predictors of variation were considered to be age, dose, and the interaction between age and dose. Two-sided Fisher's exact tests were used to assess the distributions of enzyme-inducing AEDs versus non-enzyme-inducing AEDs in the two age groups (2-5 years and 6-12 years) and two dose groups (5 and 15 mg/kg).
For part II, all AEs were summarized using a modified Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) body system. The frequency of AEs was summarized by occurrence, severity, and relationship to oxcarbazepine treatment. The number of patients with AEs, drug-related AEs, serious AEs, and study withdrawals due to AEs was also evaluated. Laboratory data summarized by visit were assessed using descriptive statistics. The change in seizure frequency was evaluated by descriptive statistics (group size, mean and standard deviation, and minimum and maximum). Trough plasma MHD concentrations were also summarized by descriptive statistics.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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2 concomitant AEDs. This patient group is typical of inadequately controlled patient populations.11,16-19
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Most patients (72%) were classified with focal/partial-epilepsy syndromes, as defined by the International League against Epilepsy classification criteria.20 Complex partial seizures were the most common seizure type (34%). Concomitant AEDs were used by all but 1 patient in the study (Table I). The most frequently used concomitant AEDs (>25%) were carbamazepine (46%), valproic acid (30%), phenytoin (26%), and vigabatrin (26%) (Table II).
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Of the 112 patients treated in the study, 80 (71%) completed the maintenance period and 32 (29%) discontinued oxcarbazepine treatment (Table III). The most common reason for discontinuation was unsatisfactory therapeutic response (n = 26; 23%). Six (5%) patients discontinued due to AEs. Of the 80 patients who completed the maintenance period, 66 (83%) continued oxcarbazepine treatment in the 12-month follow-up period, and 47 (71%) patients completed the follow-up period. Nineteen of 66 (29%) patients discontinued the follow-up period: 17 patients discontinued because of unsatisfactory therapeutic response, 1 discontinued for noncompliance, and 1 was lost to follow-up.
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Protocol Deviations
Two patients who were above the upper age limit of 12 years were allowed entry into the study; however, they were excluded from the efficacy analysis. Thirteen patients whose body weights exceeded values more than 2 standard deviations above or below the normal mean for their age entered the study. Three patients with myoclonic epilepsy did not meet the inclusion criteria for partial-onset and/or generalized atonic, tonic, or tonic-clonic seizures but were enrolled into the study.
Pharmacokinetics
Part I: Single-Dose Pharmacokinetics
The pharmacokinetic analysis included 13 patients 2 to 5 years of age and 18 patients 6 to 12 years of age. Mean plasma MHD concentrations by age and dose group are shown in Figure 1. Plasma MHD concentrations were markedly higher in all children receiving 15 mg/kg oxcarbazepine compared with 5 mg/kg oxcarbazepine, regardless of age. However, in both dose groups, plasma MHD concentrations declined more rapidly in younger children than in older children. Pharmacokinetic parameters are shown in Table IV. Age and oxcarbazepine dose influenced both oxcarbazepine and MHD parameters; however, the effects were most pronounced for MHD.
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Dose-adjusted mean specific Cmax values for MHD decreased significantly with increasing dose (P = .0001). However, there was no influence of age on the mean specific Cmax and no interaction between age and dose. At both oxcarbazepine doses, the mean specific AUC(0-48) for MHD was approximately 30% lower in younger children compared with older children (P = .0081). Mean specific AUC(0-48) was similar between doses, and no interaction between age and dose was apparent. Mean MHD t1/2 was approximately 30% lower in younger children compared with older children at both doses (P = .004) and increased by 30% to 40% with dose in both age groups (P = .02). The median tmax value was between 3 and 4 hours for both age groups at each dose. The MRT values of MHD increased significantly with age (P = .0003) and dose (P = .0002). The maximum plasma concentrations of oxcarbazepine were reached rapidly (within approximately 1 h). Thereafter, concentrations decreased rapidly. Oxcarbazepine t1/2 values, and hence MRT, could not be calculated because in most cases, the terminal segment of the curves was not well defined.
Because concomitant enzyme-inducing AEDs (eg, carbamazepine, phenytoin) have been shown to affect MHD pharmacokinetics in children,14 an analysis to determine if there were any differences in the distribution of enzyme-inducing AEDs versus non-enzyme-inducing AEDs in the single-dose pharmacokinetic study was conducted. Comparison of AED status revealed no significant differences between the two age groups at either dose. Similarly, there were no significant differences between the two dose groups for either age group. Therefore, differences in concomitant enzyme-inducing AEDs versus non-enzyme-inducing AEDs cannot explain the effects of age and dose on MHD pharmacokinetics.
Part II: Multiple-Dose Pharmacokinetics
Of the patients, 85 (22 patients 2-5 years of age and 63 patients 6-12 years of age) were included in the pharmacokinetic analysis. Seventy children completed the titration and maintenance periods (180 days), with a mean duration of 154 days (range = 2-289 days) for the entire cohort.
Oxcarbazepine Doses Administered
For the younger children (n = 17), the maintenance dose ranged from 18 to 68 mg/kg/day (mean = 43.7 ± 12.9 mg/kg/day), equivalent to 300 to 1050 mg/day oxcarbazepine. For the older children (n = 53), the maintenance dose ranged from 11 to 60 mg/kg/day (mean = 31.6 ± 12.5 mg/kg/day), equivalent to oxcarbazepine doses of 300 to 2400 mg/day. There was a statistically significant decrease in oxcarbazepine dose with increasing age (n = 70, P = .0006). The mean daily oxcarbazepine dose was 38% higher in the younger children compared with the older children. There were no marked differences in mean daily dose between males and females.
Steady-State Plasma MHD Concentrations
Steady-state trough plasma MHD concentrations tended to increase with the daily oxcarbazepine dose (mg/kg) for all ages but varied widely among patients and between age groups for any specific dose level (Figure 2). Mean specific trough plasma oxcarbazepine concentrations at steady state were approximately 2% of the mean specific trough plasma MHD concentrations for both age groups; these findings were similar to those observed in adults.21 Mean specific trough plasma MHD concentrations were 34% lower in the younger children (0.31 ± 0.13 [µmol/L]/[µmol/kg]; n = 17) compared with the older children (0.47 ± 0.22 [µmol/L]/[µmol/kg]; n = 53), suggesting a slightly higher rate of elimination of MHD in younger children. Mean specific plasma MHD concentrations were lower in patients stabilized on concomitant AEDs known to induce hepatic enzymes (eg, carbamazepine, phenytoin) compared with patients stabilized on non-enzyme-inducing AEDs. In the younger children, mean specific plasma MHD concentrations were 0.30 ± 0.13 (µmol/L)/(µmol/kg) in patients stabilized on enzyme-inducing concomitant AEDs (n = 13) and 0.34 ± 0.14 (µmol/L)/(µmol/kg) in those stabilized on non-enzyme-inducing AEDs (n = 4). Mean specific MHD concentrations in the older children were 0.41 ± 0.19 (µmol/L)/(µmol/kg) in patients stabilized on enzyme-inducing AEDs (n = 37) compared with 0.60 ± 0.22 (µmol/L)/(µmol/kg) in those stabilized on non-enzyme-inducing AEDs (n = 16). For patients stabilized on non-enzyme-inducing AEDs, mean plasma MHD concentrations were approximately 62% lower in the younger children and 33% lower in the older children, compared with mean specific plasma MHD concentrations in adults (0.89 ± 0.22 [µmol/L]/[µmol/kg]; data on file, Novartis).
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Safety and Tolerability
All patients who received oxcarbazepine (n = 112) were included in the safety and tolerability analyses. Of the patients, 84 (75%) experienced one or more AEs. The most commonly (>15%) experienced AEs were somnolence and vomiting (Table V). Six patients experienced dermatitis or skin rash of mild or moderate severity, but no such AE led to discontinuation of treatment. Most AEs (67%) were rated as mild or moderate by the investigator. The majority of AEs occurred during the first 4 to 6 weeks of the titration period. For 22 patients (20%), a reduction in oxcarbazepine dose was required to improve tolerability. Six patients (5%) discontinued the study prematurely due to one or more AEs. All 6 discontinuing patients discontinued during the titration period, and 5 of 6 were in the older age group. In most patients discontinuing due to AEs, more than one AE was reported. The most common AEs reported in these patients were somnolence (n = 3) and diplopia (n = 2), with dizziness and giddiness, moderate sleep disorder, awareness disturbance, hemiplegia, increased seizure frequency, severe weight gain, and headache all being reported once. Concomitant AEDs in these discontinuing patients included carbamazepine (n = 4) and vigabatrin (n = 3).
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Serious AEs were reported for 15 patients, of whom 13 required hospitalization. Three serious AEs were regarded by the investigator as possibly treatment related and were complex partial with secondarily generalized seizures, hepatitis, and worsening of preexisting eczema. No clinically notable changes in laboratory values, vital signs, or physical examination were observed with oxcarbazepine treatment.
Efficacy
The change in seizure frequency from baseline to the end of treatment was assessed for 110 patients. Two patients were excluded from the efficacy analysis because they exceeded the upper age limit. Forty-nine children (45%) had a 50% or greater reduction in seizure frequency during oxcarbazepine treatment, of whom 15 (14%) were seizure free. Seizure frequency was unchanged in 24 children (22%). Twenty-two (20%) children experienced an increase in seizure frequency. One patient experienced an episode of status epilepticus, which was considered unlikely to be related to treatment with oxcarbazepine. Six patients were admitted to hospital for seizure worsening, but only one case was considered to be possibly related to treatment.
Although patient numbers were too small to make definite conclusions, there appears to be no clear benefit of oxcarbazepine treatment in patients with West syndrome (n = 4) or myoclonic epilepsy (n = 3). Six of 7 patients with Lennox-Gastaut syndrome experienced a reduction in seizure frequency.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This study was carried out in children typical of inadequately controlled patient populations.11,16-19 The results of the present study indicate that after a single oxcarbazepine dose of 15 mg/kg, peak plasma concentrations and t1/2 of MHD in children 6 to 12 years of age are similar to those observed in adults. Significant reductions in AUC, t1/2, and MRT values for MHD were observed in children 2 to 5 years of age compared with older children after single oxcarbazepine doses of 5 and 15 mg/kg. Furthermore, after a single dose of oxcarbazepine, plasma MHD concentrations decreased more rapidly in younger children compared with older children. Following multiple doses in children, plasma MHD concentrations tended to increase with oxcarbazepine dose, as is seen in adults. When adjusted for dose, plasma MHD concentrations were lower in younger children compared with older children. Furthermore, when patients were titrated to an effective and well-tolerated dose of oxcarbazepine, younger children required an approximately 38% higher daily dose (mg/kg) for maximum therapeutic benefit. Despite higher doses, corresponding trough plasma MHD concentrations were 34% lower than those achieved in older children.
These data suggest that the pharmacokinetics of oxcarbazepine and MHD in children 2 to 5 years of age may be related to a higher rate of metabolism in younger children. Age-related differences in MHD pharmacokinetics noted in the current study are consistent with the increased weight-normalized clearance of MHD seen in younger children compared with older children and adults.14 Increased clearance would be reflected in reduced AUC values, as observed in this study. Similar increased rates of clearance in young children compared with older children or adults have been reported for other AEDs.23-25
In both age groups, mean specific MHD concentrations were lower in children receiving concomitant enzyme-inducing AEDs compared with those receiving non-enzyme-inducing AEDs. This is consistent with the study of Sallas and colleagues,14 in which the estimated apparent clearance of MHD was increased in 3- to 17-year-old children coadministered enzyme-inducing AEDs. The effects of enzyme-inducing AEDs appear to be similar in infants and young children who are 1 month to 4 years of age.26
Oxcarbazepine was safe and generally well tolerated in children with inadequately controlled epilepsy, with a low rate of discontinuations due to AEs. Although the most frequent AEs in this study appear to have a high rate of incidence (Table V), these results are consistent with those reported in trials of other AEDs in children, in which the most frequent AEs occurred in > 20% of patients.16,17,27 In placebo-controlled trials of oxcarbazepine, lamotrigine, and topiramate, AE profiles were similar between active drug- and placebo-treated children and were consistent with the AE profile reported in this study.11,16,17 Furthermore, the dose of oxcarbazepine was increased until patients were rendered seizure free or exhibited AEs. The most commonly reported AEs in children receiving combination therapy were related to the central nervous system and the gastrointestinal system.
In general, most AEs were observed within the first 4 to 6 weeks of the titration period. There was no evidence of hyponatremia in this study, confirming that oxcarbazepine may have a favorable profile regarding hyponatremia in the pediatric population.28 The relationship between treatment with oxcarbazepine and AEs could not be determined, as AE data for a matching control group were not available for comparison. However, of the 6 patients who discontinued oxcarbazepine treatment due to AEs (predominately somnolence), most were also receiving concomitant AED treatment with carbamazepine and/or vigabatrin.
The tolerability of oxcarbazepine treatment did not appear to be affected by patient age, although the number of discontinuations due to AEs was small. Maturation is known to influence the metabolism of drugs, and clinicians should be aware of changes in a child's response to a given dose of oxcarbazepine with advancing age, especially when other AEDs are administered concomitantly.
Although the study was not designed to rigorously evaluate the potential therapeutic benefit of oxcarbazepine, seizure frequency appeared to be improved in 58% of children with inadequately controlled epilepsy. In a placebo-controlled trial of children with partial seizures, which included the subtypes of simple, complex, and partial seizures evolving to secondarily generalized seizures, a greater reduction in seizure frequency, regardless of type, with oxcarbazepine compared with placebo was reported.11 The data collected in this study suggest that there is no evidence of an improvement in patients with either West syndrome (n = 4) or myoclonic epilepsies (n = 3), a finding similar to observations reported for carbamazepine; there may be some benefit for patients with Lennox-Gastaut syndrome (n = 7). The numbers of patients with syndromatic generalized epilepsies, however, were small, and no conclusion can been drawn from this open study. In a separate study that included children with both partial seizures and generalized tonic-clonic seizures, the proportion of seizure-free oxcarbazepine-treated patients was independent of seizure type (60% vs 59%, respectively).10
This study confirms that oxcarbazepine is well tolerated as combination therapy in children 2 to 12 years of age with inadequately controlled epilepsy. The pharmacokinetic analyses indicated that higher doses of oxcarbazepine may be needed in younger children (2-5 years of age) compared with older children ( 6 years of age) to achieve comparable plasma MHD concentrations. Based on these findings, body weight-normalized daily doses to be administered to children < 6 years of age should be increased by up to 50% compared to doses administered to older children and adults. Furthermore, combination therapy with oxcarbazepine appeared to improve seizure frequency in children with inadequately controlled epilepsy.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication July 7, 2003; Revised version accepted April 20, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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