European Journal of Clinical Pharmacology © by Springer-Verlag 1977
Europ. J. din. Pharmacol.11, 129-133 (1977)
Carbamazepine and Its lO,11-Epoxide in Children and Adults with Epilepsy S. Pynn6nen, M. Sillanp/i/i 1, H. Frey 2 and E. Iisalo Departmentsof Pharmacology,XPaediatricsand 2Neurology,Universityof Turku, Turku, Finland
Summary. The plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 37 children and 13 adults with epilepsy during maintenance therapy. The children formed relatively more of the epoxy metabolite than adults. The daily dose, expressed as mg/kg or mg/m 2, showed a statistically significant correlation with blood level in children, but not in adults. The cerebrospinal fluid concentrations of carbamazepine and carbamazepine- 10,11-epoxide in nine children were 33 and 41 per cent, respectively, of the concomitant plasma level. Key words: carbamazepine, carbamazepine-10,11epoxide, plasma concentration, CSF concentration, children, adult.
One of the metabolic pathways of carbamazepine (CBZ) is epoxidation in the liver [1], which results in carbamazepine- 10,11-epoxide (CBZ-E). The latter is biologically active, at least in rats [2], in whom it is as potent as its parent compound against electroshock induced seizures [2]. This active metabolite may account for the lack of correlation between the clinical antiepileptic effect of CBZ and the concentration of the parent compound in plasma [3, 4]. As a preliminary report had suggested higher CBZ-E levels in children than in adults [5], the ratio of CBZ-E to CBZ has been compared in children and adults.
Material and Methods The series of 50 subjects (Tables 1, 2) consisted of 37 children (age 0.3-15, mean 6.8 years) and 13 adults (age 16-57, mean 36.9 years) with various types of epilepsy. The clinical data are summarized in Table 3. Because the follow-up periods differed greatly, no
attempt was made at this stage of study to correlate the plasma level of the drug with its clinical effects. CBZ was administered bid., either alone or, in some cases, combined with other antiepileptic drugs. The latter patients have been indicated separately in Table 1. The average dosage of CBZ was 13.7 mg/kg (range 3.1-25.8 mg/kg) in epileptic children and 11.4 mg/kg (range 6.5-22.2 mg/kg) in adults. The samples were taken in the steady state phase, i. e. after a period of at least five times the half-life of CBZ [6, 7]. Before sampling, the mean duration of therapy in the children was 12.7 weeks, and in the adult epileptics 8.4 weeks. For technical reasons, blood samples had to be taken from out-patients 6+2 hours after the morning dose. Under these conditions the plasma levels of CBZ represent peak values [8]. In nine epileptic children the concentrations of CBZ and CBZ-E were measured in plasma and CSF collected at the same time. The analysis of CBZ and CBZ-E was by a direct gas chromatographic method [5, 9]. After extraction CBZ was detected with a flame ionization detector (FID) and CBZ-E with an alkali flame ionization detector (A-FID). The volume required of plasma and CSF was 0.5 ml. The recoveries of CBZ and CBZ-E from plasma and CSF were 98 per cent and 73 per cent, respectively. Under hot GLC conditions, both CBZ-E and 10,11-dihydroxy CBZ (also a metabolite of CBZ) give the same degradation product [10], but the extraction procedure completely eliminates the 10,11-dihydroxy derivative. Student's t-test was used for statistical analysis.
Results The clinical and laboratory findings in each patient are presented in Tables 1 and 2. Neither the dosage of CBZ nor the corresponding plasma levels differed
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S. Pynn6nen et al.: Carbamazepine in Epileptic Children and Adults Table 3. Clinical indications for carbamazepine therapy in 37 children and 13 adults Neurological disorder
Children
Primary grand mal seizures Partial seizures Psychomotor seizures Minor motor seizures
10 9 19 5
-
43
13
31 6
13 -
Single seizures Combined seizures
Adults 3 2 8
Table 4. The correlation coefficients between dosage and blood level in 37 children and 13 adults
two groups are shown in Table 4. The children had higher correlation coefficients than adults; every coefficient in a child was statistically significant (p
Europ. J. din. Pharmacol.11, 129-133 (1977)
Carbamazepine and Its lO,11-Epoxide in Children and Adults with Epilepsy S. Pynn6nen, M. Sillanp/i/i 1, H. Frey 2 and E. Iisalo Departmentsof Pharmacology,XPaediatricsand 2Neurology,Universityof Turku, Turku, Finland
Summary. The plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 37 children and 13 adults with epilepsy during maintenance therapy. The children formed relatively more of the epoxy metabolite than adults. The daily dose, expressed as mg/kg or mg/m 2, showed a statistically significant correlation with blood level in children, but not in adults. The cerebrospinal fluid concentrations of carbamazepine and carbamazepine- 10,11-epoxide in nine children were 33 and 41 per cent, respectively, of the concomitant plasma level. Key words: carbamazepine, carbamazepine-10,11epoxide, plasma concentration, CSF concentration, children, adult.
One of the metabolic pathways of carbamazepine (CBZ) is epoxidation in the liver [1], which results in carbamazepine- 10,11-epoxide (CBZ-E). The latter is biologically active, at least in rats [2], in whom it is as potent as its parent compound against electroshock induced seizures [2]. This active metabolite may account for the lack of correlation between the clinical antiepileptic effect of CBZ and the concentration of the parent compound in plasma [3, 4]. As a preliminary report had suggested higher CBZ-E levels in children than in adults [5], the ratio of CBZ-E to CBZ has been compared in children and adults.
Material and Methods The series of 50 subjects (Tables 1, 2) consisted of 37 children (age 0.3-15, mean 6.8 years) and 13 adults (age 16-57, mean 36.9 years) with various types of epilepsy. The clinical data are summarized in Table 3. Because the follow-up periods differed greatly, no
attempt was made at this stage of study to correlate the plasma level of the drug with its clinical effects. CBZ was administered bid., either alone or, in some cases, combined with other antiepileptic drugs. The latter patients have been indicated separately in Table 1. The average dosage of CBZ was 13.7 mg/kg (range 3.1-25.8 mg/kg) in epileptic children and 11.4 mg/kg (range 6.5-22.2 mg/kg) in adults. The samples were taken in the steady state phase, i. e. after a period of at least five times the half-life of CBZ [6, 7]. Before sampling, the mean duration of therapy in the children was 12.7 weeks, and in the adult epileptics 8.4 weeks. For technical reasons, blood samples had to be taken from out-patients 6+2 hours after the morning dose. Under these conditions the plasma levels of CBZ represent peak values [8]. In nine epileptic children the concentrations of CBZ and CBZ-E were measured in plasma and CSF collected at the same time. The analysis of CBZ and CBZ-E was by a direct gas chromatographic method [5, 9]. After extraction CBZ was detected with a flame ionization detector (FID) and CBZ-E with an alkali flame ionization detector (A-FID). The volume required of plasma and CSF was 0.5 ml. The recoveries of CBZ and CBZ-E from plasma and CSF were 98 per cent and 73 per cent, respectively. Under hot GLC conditions, both CBZ-E and 10,11-dihydroxy CBZ (also a metabolite of CBZ) give the same degradation product [10], but the extraction procedure completely eliminates the 10,11-dihydroxy derivative. Student's t-test was used for statistical analysis.
Results The clinical and laboratory findings in each patient are presented in Tables 1 and 2. Neither the dosage of CBZ nor the corresponding plasma levels differed
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131
S. Pynn6nen et al.: Carbamazepine in Epileptic Children and Adults Table 3. Clinical indications for carbamazepine therapy in 37 children and 13 adults Neurological disorder
Children
Primary grand mal seizures Partial seizures Psychomotor seizures Minor motor seizures
10 9 19 5
-
43
13
31 6
13 -
Single seizures Combined seizures
Adults 3 2 8
Table 4. The correlation coefficients between dosage and blood level in 37 children and 13 adults
two groups are shown in Table 4. The children had higher correlation coefficients than adults; every coefficient in a child was statistically significant (p
