Ki netics of carbamazepine and its 10, 11-epoxide metabolite in children The plasma steady-state concentration of carbamazepine (CBZ) and its metabolite (carbamazepine-l0, I I-epoxide, CBZ-epoxide) was assessed in 43 children (2-15 yr) on CBZ (Tegretol) treatment. Twenty of the children received combined treatment with other anticonvulsant drugs simultaneously. The plasma concentrations were in the same range as had been found in adult patients on corresponding doses. Only a weak correlation was noted between dose and plasma CBZ concentration in the group of children on single-drug treatment, and there was no correlation in the group of children on combined drug regimen. Plasma levels of CB Z correlated with those of the metabolite. Children on combined treatment had lower CBZ concentration and, expressed as percent of the parent drug, the metabolite concentration was significantly higher than in children treated only with CBZ. In 2 children the plasma half-life of CB Z was estimated and found to be slightly shorter than has previously been reported in adults. In evaluating the plasma level-effect relationship of CBZ, the plasma concentration of the CBZ-epoxide should be measured simultaneously because of its anticonvulsant effect and interindividual variability.
Anders Rane, M.D., Bengt Hojer, M.D., and John T. Wilson, M.D.* Huddinge, Sweden Department of Clinical Pharmacology and Pediatrics, Karolinska Institutet, Huddinge University Hospital
Carbamazepine is an effective drug for the treatment of patients with trigeminal neuralgia,3,4 grand mal and psychomotor epilepsy,5,6,15 and tabetic lightning pains12 and paresthesia associated with Lhermitte's sign.l1 Despite its widespread use, relatively little is
Supported by grants from the Swedish Medical Research Council (04X-4496, 3902-03B) and the Association of the Swedish Pharmaceutical Industry. Received for publication Sept. 29. 1975. Accepted for publication Nov. 11. 1975. Reprint requests to: Dr. A. Rane. Division of Clinical Pharmacology. Vanderbilt University School of Medicine. Nashville. Tenn. 37232. 'Present address: Department of Pediatrics. Vanderbilt Medical Center, Nashville, Tenn. 37232; recipient of a Research Career Development Award from the NIH (K4-H842, 539).
276
known about its disposition in man. The metabolic fate of CBZ was largely unknown until the 1O,1l-epoxide 14 and the 1O,II-transdihydroxydihydro-metabolite 1 were identified in the urine of man. Twenty to thirty percent of a single oral dose of CBZ is excreted in the urine as 10, 11-transdihydroxydihydrocarbamazepine, and CBZ-IO,II-epoxide and other metabolic products have also been found in the urine of man. 13 The disposition of CBZ has been studied in adult volunteers 19 ,21 and patients. 9 ,10,19 Plasma levels of CBZ have recently been reported in children,17 as were the concentrations of the epoxide in 3 children, between 8 and 14 yr of age. 19 However, all of these children were
Carbamazepine kinetics in children
Volume 19 Number 3
277
Table I. Neurological disorders of the children and additional diagnoses *
Neurological disorder
Group A
Group B
Children with:
Children with:
Additional diagnosis
Neurological disorder
Neurological disorder
Number Grand mal epilepsy Psychomotor epilepsy Grand mal and psychomotor epilepsy Focal motor epilepsy Minor motor epilepsy Suspected or nonspecific epilepsy Behavior disorder Mental retardation Other conditions
4
Total number of subjects
23
I
Additional diagnosis
Number 8 3 4
6 2 I I
3
6 I 8
4
1 3
2
2
1
20
*The figures indicate number of children of each diagnosis either given only CBZ (Group A) or other drugs as well (Group B).
also treated with other antiepileptic drugs. Since anticonvulsant activity is exerted to about the same degree by equimolar doses of CBZ and its 1O,II-epoxide in experimental animals,18 it is of interest to study both compounds in patients treated with CBZ. We here report the plasma concentrations of CBZ and CBZ-epoxide during steady-state conditions in 43 epileptic children. Children treated only with CBZ showed a higher CBZ-epoxide to CBZ level ratio as compared to that from children on a combined drug regimen. Patients
Forty-three children who were between 1% and 15 yr of age, were induded in the study. The children were both outpatients and inpatients at the Pediatric Clinic of Huddinge University Hospital and were included in the study when plasma CBZ analysis was requested by their physician. A few patients were removed from the study because of poor drug compliance. The patients were divided into two categories, those without (Group A) and those with (Group B) concomitant drug therapy. *
*Phenobarbital, phenytoin. nitrazepam, diazepam, c1onazepam, ethosuximide, mephenetoin, brompheniramine, phenylpropanolamine. or, in one case, cyclohexyl-methylaminopropanphenylethylbarbiturate. In most cases, the patients were on one or two of the first three drugs.
The clinical data are summarized in Table I. Blood samples were obtained not earlier than 1 mo after the last dose adjustment of either CBZ or other drugs (see Table I). In 2 patients, the CBZ treatment was withdrawn and the plasma half-life determined. One child, a 13-yr-old girl, had been treated several months for therapy-resistant headache without any effect. Another patient, a 10-yr-old boy, developed a general allergic exanthema ascribed to CBZ on the tenth day of therapy and the treatment had to be discontinued. He is not included in either group of subjects since the treatment lasted for less than 1 moo In these cases, the parents were informed about the purpose of drawing blood samples and their consent was obtained. Methods
Blood samples were always obtained immediately before the morning dose in heparinized tubes. Capillary blood samples were obtained in lieu of venous samples when halflife determinations were made. Two ml plasma was separated by centrifugation and frozen at - 200 C until analysis. CBZ is stable under these conditions for several months, whereas CBZ-epoxide is slowly degraded. After 3 mo storage in plasma at -200 C, the concentration of the epoxide decreased by not more than
278
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Table 11. Plasma concentrations of CB Z and its 1O,1l-epoxide metabolite and drug doses in children without (Group A) or with (Group B) concomitant drug therapy *
Group
Daily dose (mg/kg)
CB Z-concentration
CB Z-epoxide concentration
( f.Lg/ml)
f.Lg/ml
I
% ojCBZ
A (n = 23)
12.4 :': 4.3 (4-24)
5.4 :': 2. I (1.7-9.9)
0.67 :': 0.37 (0.09-1.60)
11.9:': 4.6 (5.3-23.1)
B
14.3 :': 5.6 (4-30)
3.7 :': 2.1 t (1.4-10.7)
0.78:': 0.48* (0.27-2.31)
23.8 ± 15.4t (I 1.0-81.3)
(n = 20)
CBZ: carbamazepine. CBZ-epoxide: carbamazepine·l0.ll·epoxide. The values indicate mean ± S.D. The ranges are given in parentheses.
* Nineteen of the 20 patients in the latter group were treated with other anticonvulsants (see "Patients" and Methods"). Tables with individual plasma concentrations and the complete drug therapy of all patients are available upon request. t Different from corresponding value in Group A (p < 0.01). tNot different from corresponding value in Group A (p > 0.05).
10%. * This was considered acceptable for the purpose of this study, and all analyses were therefore performed within this time limit. CBZ and its epoxide were analyzed with the use of high-speed liquid chromatography according to Eichelbaum and Bertilsson. 8 *Ringberger. V. A.: Unpublished observations in this labora· tory.
Results
Most patients in both groups were treated with 10 to 20 mg CBZ/kg body weight daily, which is recommended by the manufacturer (Table 11). Neither the dose nor plasma concentration of the drug varied with age. The subjects were not divided into different age groups but were compared solely on the basis of the use of single or combined drug therapy.
Carbamazepine kinetics in children
Volume 19 Number 3
279
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Fig. 2. Relation between daily dose of CBZ and the achieved plasma concentration during steadystate in children treated with CBZ alone (Group A) or in combination with other antiepileptic drug(s) (Group B).
The mean plasma concentration of CBZ in Group A was 5.4 ± 2.1 (SD) p,g/ml of the 23 patients. Plasma concentrations below 3.7 p,g/ ml were seen in only 3 of the 23 patients. The mean plasma concentration of CBZ in Group B
was 3.7 ± 2.Ip,g/ml, and 13 of the 20 patients had plasma concentrations below 3.7 p,g/ml. The means are significantly different. The plasma concentrations of the CBZepoxide were much lower than those of the
280
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Anders Rane, M.D., Bengt Hojer, M.D., and John T. Wilson, M.D.* Huddinge, Sweden Department of Clinical Pharmacology and Pediatrics, Karolinska Institutet, Huddinge University Hospital
Carbamazepine is an effective drug for the treatment of patients with trigeminal neuralgia,3,4 grand mal and psychomotor epilepsy,5,6,15 and tabetic lightning pains12 and paresthesia associated with Lhermitte's sign.l1 Despite its widespread use, relatively little is
Supported by grants from the Swedish Medical Research Council (04X-4496, 3902-03B) and the Association of the Swedish Pharmaceutical Industry. Received for publication Sept. 29. 1975. Accepted for publication Nov. 11. 1975. Reprint requests to: Dr. A. Rane. Division of Clinical Pharmacology. Vanderbilt University School of Medicine. Nashville. Tenn. 37232. 'Present address: Department of Pediatrics. Vanderbilt Medical Center, Nashville, Tenn. 37232; recipient of a Research Career Development Award from the NIH (K4-H842, 539).
276
known about its disposition in man. The metabolic fate of CBZ was largely unknown until the 1O,1l-epoxide 14 and the 1O,II-transdihydroxydihydro-metabolite 1 were identified in the urine of man. Twenty to thirty percent of a single oral dose of CBZ is excreted in the urine as 10, 11-transdihydroxydihydrocarbamazepine, and CBZ-IO,II-epoxide and other metabolic products have also been found in the urine of man. 13 The disposition of CBZ has been studied in adult volunteers 19 ,21 and patients. 9 ,10,19 Plasma levels of CBZ have recently been reported in children,17 as were the concentrations of the epoxide in 3 children, between 8 and 14 yr of age. 19 However, all of these children were
Carbamazepine kinetics in children
Volume 19 Number 3
277
Table I. Neurological disorders of the children and additional diagnoses *
Neurological disorder
Group A
Group B
Children with:
Children with:
Additional diagnosis
Neurological disorder
Neurological disorder
Number Grand mal epilepsy Psychomotor epilepsy Grand mal and psychomotor epilepsy Focal motor epilepsy Minor motor epilepsy Suspected or nonspecific epilepsy Behavior disorder Mental retardation Other conditions
4
Total number of subjects
23
I
Additional diagnosis
Number 8 3 4
6 2 I I
3
6 I 8
4
1 3
2
2
1
20
*The figures indicate number of children of each diagnosis either given only CBZ (Group A) or other drugs as well (Group B).
also treated with other antiepileptic drugs. Since anticonvulsant activity is exerted to about the same degree by equimolar doses of CBZ and its 1O,II-epoxide in experimental animals,18 it is of interest to study both compounds in patients treated with CBZ. We here report the plasma concentrations of CBZ and CBZ-epoxide during steady-state conditions in 43 epileptic children. Children treated only with CBZ showed a higher CBZ-epoxide to CBZ level ratio as compared to that from children on a combined drug regimen. Patients
Forty-three children who were between 1% and 15 yr of age, were induded in the study. The children were both outpatients and inpatients at the Pediatric Clinic of Huddinge University Hospital and were included in the study when plasma CBZ analysis was requested by their physician. A few patients were removed from the study because of poor drug compliance. The patients were divided into two categories, those without (Group A) and those with (Group B) concomitant drug therapy. *
*Phenobarbital, phenytoin. nitrazepam, diazepam, c1onazepam, ethosuximide, mephenetoin, brompheniramine, phenylpropanolamine. or, in one case, cyclohexyl-methylaminopropanphenylethylbarbiturate. In most cases, the patients were on one or two of the first three drugs.
The clinical data are summarized in Table I. Blood samples were obtained not earlier than 1 mo after the last dose adjustment of either CBZ or other drugs (see Table I). In 2 patients, the CBZ treatment was withdrawn and the plasma half-life determined. One child, a 13-yr-old girl, had been treated several months for therapy-resistant headache without any effect. Another patient, a 10-yr-old boy, developed a general allergic exanthema ascribed to CBZ on the tenth day of therapy and the treatment had to be discontinued. He is not included in either group of subjects since the treatment lasted for less than 1 moo In these cases, the parents were informed about the purpose of drawing blood samples and their consent was obtained. Methods
Blood samples were always obtained immediately before the morning dose in heparinized tubes. Capillary blood samples were obtained in lieu of venous samples when halflife determinations were made. Two ml plasma was separated by centrifugation and frozen at - 200 C until analysis. CBZ is stable under these conditions for several months, whereas CBZ-epoxide is slowly degraded. After 3 mo storage in plasma at -200 C, the concentration of the epoxide decreased by not more than
278
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Clinical Phannacology and Therapeutics
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Table 11. Plasma concentrations of CB Z and its 1O,1l-epoxide metabolite and drug doses in children without (Group A) or with (Group B) concomitant drug therapy *
Group
Daily dose (mg/kg)
CB Z-concentration
CB Z-epoxide concentration
( f.Lg/ml)
f.Lg/ml
I
% ojCBZ
A (n = 23)
12.4 :': 4.3 (4-24)
5.4 :': 2. I (1.7-9.9)
0.67 :': 0.37 (0.09-1.60)
11.9:': 4.6 (5.3-23.1)
B
14.3 :': 5.6 (4-30)
3.7 :': 2.1 t (1.4-10.7)
0.78:': 0.48* (0.27-2.31)
23.8 ± 15.4t (I 1.0-81.3)
(n = 20)
CBZ: carbamazepine. CBZ-epoxide: carbamazepine·l0.ll·epoxide. The values indicate mean ± S.D. The ranges are given in parentheses.
* Nineteen of the 20 patients in the latter group were treated with other anticonvulsants (see "Patients" and Methods"). Tables with individual plasma concentrations and the complete drug therapy of all patients are available upon request. t Different from corresponding value in Group A (p < 0.01). tNot different from corresponding value in Group A (p > 0.05).
10%. * This was considered acceptable for the purpose of this study, and all analyses were therefore performed within this time limit. CBZ and its epoxide were analyzed with the use of high-speed liquid chromatography according to Eichelbaum and Bertilsson. 8 *Ringberger. V. A.: Unpublished observations in this labora· tory.
Results
Most patients in both groups were treated with 10 to 20 mg CBZ/kg body weight daily, which is recommended by the manufacturer (Table 11). Neither the dose nor plasma concentration of the drug varied with age. The subjects were not divided into different age groups but were compared solely on the basis of the use of single or combined drug therapy.
Carbamazepine kinetics in children
Volume 19 Number 3
279
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The mean plasma concentration of CBZ in Group A was 5.4 ± 2.1 (SD) p,g/ml of the 23 patients. Plasma concentrations below 3.7 p,g/ ml were seen in only 3 of the 23 patients. The mean plasma concentration of CBZ in Group B
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280
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