Diurnal Variation of Carbamazepine and Carbamazepine-10,11-epoxide in Plasma and Saliva in Children With Epilepsy: A Comparison Between Conventional and Slow-Release Formulations Orvar
Eeg-Olofsson, MD, PhD;
Heimo L.
Jan Arvidsson, MD; Per-Åke Grahn, MD;
Nilsson, PhD; Bernt Tonnby, MD; Hans
Gylje, MD;
Christer Larsson, MD;
Lars Norén, MD
Abstract overcome the problems of interdosage fluctuations of body fluid concentrations of carbamazepine, a slow-release formulation has been developed. In an open, controlled, within-patient study, the diurnal plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 25 epileptic children first treated with conventional carbamazepine tablets (Tegretol) and then with the Tegretol slow-release preparation. The diurnal plasma concentration curves during treatment with the slow-release formulation showed significantly less variation over 24 hours than during treatment with the ordinary preparation, as measured by the fluctuation index. Mean concentration values also differed significantly, which is explained by a somewhat reduced bioavailability (22% less) of the slow-release formulation. There were no differences in efficacy and tolerability between the two formulations, but there was a clear-cut reduction of reported side effects, especially tiredness, on treatment with the slow-release formulation. For that reason, the slow-release formulation should be a major advantage in treating children with epilepsy, in order to avoid interference with cognitive functions. In 12 children, simultaneous measurements of the concentration of carbamazepine and its epoxide in saliva were made and compared with the plasma values. As expected, the concentration curves corresponded, indicating that saliva sampling is an appropriate alternative for monitoring the concentration of carbamazepine. All children remained on the slow-release J Child Neurol 1990;5:159-165). preparation after the trial and were followed up for 12 months or more. (
In order to
several years, carbamazepine has been as an effective antiepileptic drug in the treatment of both partial and generalized tonic-clonic seizures. Usually, a regimen of a twice daily drug intake has been preferred. However, the usefulness
or
Fused
Received May 23, 1989. Received revised August 16, 1989. for publication Sept 7, 1989. From the Department of Pediatrics (Dr Eeg-Olofsson), Faculty of Health Sciences, Linköping, CIBA-GEIGY AB (Dr Nilsson), Pharmaceuticals Division, Gothenburg, and the Departments of Pediatrics, Central Hospitals of Halmstad (Dr Tonnby), Jönköping (Dr Arvidsson), Vänersborg (Dr Grahn), Västerås (Dr Gylje, Dr Norén), and Skävde (Dr Larsson), Sweden. Address correspondence to Dr Eeg-Olofsson, The National Center for Epilepsy, PO Box 900, N-1301 Sandvika, Norway.
Accepted
of the
drug is influenced by diurnal fluctuations in the plasma levels, leading to transitory side effects in some individuals. This has been noticed especially in &dquo;
adults .5- To avoid this the dividing daily intake into three, or more doses has been tried. 7 This type of four, is and sometimes unreliable, and regimen impractical there is a risk of noncompliance. A slow-release formulation of carbamazepine should produce less fluctuation in the plasma level on twice daily administration. The aim of the present study is to compare the variation over 24 hours of the plasma and saliva concentrations of carbamazepine and its 10,11-epoxide in children on treatment with children 2-’ but also
in
inconvenience,
159
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
conventional carbamazepine tablets and a slow-release
preparation. Material and Methods Twenty-five children, 12 girls and 13 boys whose ages
ranged from 4 to 13 years, were included in this multicenter study in which six different Swedish pediatric departments participated. Aside from their seizure disorder, no other Informed consent for participation was received from the parents. All children were initially treated with conventional carbamazepine (Tegretol tablets 200 mg and 400 mg, CIBA-GEIGY AG) for partial or generalized tonic-clonic seizures ranging from 4 months to 10 years (median, 4.0 yr) in duration. The drug was given twice daily, at approximately 8:00 AM and 8:00 PM, and the dosage ranged from 10.0 to 35.3 mg/kg (mean, 19.1; SD, 7.5 mg/kg). Four patients were protocol violators with regard to pharmacokinetic data: two children were treated with phenobarbital and two children with acetazolamide in addition to carbamazepine. No other concomitant treatment was given. Thus, the kinetic calculations were made on data from 21 children on monotherapy, 10 girls and 11 boys aged 4 to 13 years (mean, 7.5; SD, 2.6 yr). Clinical judgments and tolerability results, however, are based on all 25 children, because we wanted to know if the slow-release preparation could influence these variables irrespectively of mono- or chronic
or
acute disease existed.
polytherapy.
Study Design design was an open, within-patient trial. The study sample was not randomly selected and therefore was subject to unknown biases. However, it is not expected that such a bias should interfere with the results of a pharmacokinetic study. All children had been treated with conventional carbamazepine for at least 4 months before the start of the trial. The patients were followed through a baseline period of 4 weeks with their present dose on a twice daily dose regimen (study period 1). Conventional carbamazepine was then shifted dose by dose to slow-release carbamazepine (Tegretol Retard tablets 200 mg, CIBA-GEIGY AG), and the patients were followed for another 4 weeks (study period 2). At the end of study periods 1 and 2 the children were hospitalized, and 24-hour profiles of the plasma (n 21) and saliva (n = 12) concentrations were taken. Samples were drawn before the morning dose was given at approximately 8:00 AM and then at one-hour intervals until 10:00 PM. Thereafter, samples were obtained The trial
=
AM. Blood and saliva were drawn In order to collect saliva, the child first had to rinse her or his mouth with fresh water. The secretion of saliva was then stimulated by chewing on Parafilm or a plastic tube. About 2 mL of saliva was collected in a glass tube.’ Blood and saliva samples were centrifuged, and the supernatant stored at -20°C. All samples from one center were analyzed at the same time. The concentrations of carbamazepine and its epoxide were assayed by a modified high-performance liquid chromatography method (G. Dahlstrbm and B. Norlander, personal communication) based on the method of Eichelbaum et al.’° Laboratory tests, including a complete blood count and liver function tests (transaminases and alkaline phosphatase), were checked at the start of both study periods.
at
2:00, 6:00, and 8:00
simultaneously.
Clinical Assessment: Efficacy and Tolerability The change in seizure frequency was recorded at the end of each study period and the overall efficacy rated on a 5-point scale (much worse, worse, same, better, much better). A general assessment of the tolerability with the scale
performed after study period 2. At the same preference for the conventional or slow-release form of the drug was obtained from the patient and parents, as well as from the treating doctor. The nature, date of onset, severity (mild not disturbing, moderate disturbing but acceptable, severe markedly disturbing), frequency, duration, and relation to treatment of any symptom observed by the medical staff or reported by the same
was
time, information about
=
=
=
parents
were
recorded.
Calculations and Statistics The
systemic relative bioavailability over 24 hours obtained by calculating the areas under the plasma concentration-time curve (24-hr AUC); the calculations were carried out by the trapezoidal rule. To achieve comparable values in one case where the 0-hour value was missing, this value was substituted by the respective 24-hour value. The same procedure was performed in 2 cases in which the 24-hour value was missing. The mean diurnal plasma concentrations were calculated as the mean peak concentrations (Cmax) and the mean lowest concentration over 24 hours (Cmin)’ To be able to compare the plasma concentration-time profiles on treatment with conventional and slow-release carbamazepine, a fluctuation index (FI) was calculated by the following formula: was
FI
Cmax Cumin
= 24-hr AUC 24
Since the number of
patients from each
center
was
low,
no
homogeneity analysis was conducted. The Student’s t-test was used for significance tests. Since no control group was present, significance tests were not used in connection with the clinical assessments.
Results Pharmacokinetics The pharmacokinetic calculations of carbamazepine and its main metabolite, the 10,11-epoxide, in plasma after treatment with conventional and slow-release formulations, respectively, are shown in Tables 1 and 2, and calculations for salivary values in Tables 3 and 4. The 24-hr AUC values of slow-release compared to conventional carbamazepine were about 22% lower (data from plasma). Treatment with slow-release carbamazepine twice daily leads to a significant reduction of mean Cmax by about 26% compared to treatment with conventional carbamazepine, and no
significant difference was seen in mean Cumin. Carbamazepine plasma levels ranged from
160
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
11.2
TABLE 1
Carbamazepine Concentrations After Treatment With Conventional and Slow-Release
Pharmacokinetic Data of Plasma
Carbamazepine*
AUC area under the curve; NS * N = 21. =
t
=
significant.
Mean ± SD.
TABLE 2 Pharmacokinetic Data of Plasma Slow-Release Carbamazepine*
area under the AUC * N = 21. =
t
not
curve;
NS
Carbamazepine-10,11-epoxide Concentrations After
=
not
Treatment With Conventional and
significant.
’
>
Mean ± SD. ’
TABLE 3 Pharmacokinetic Data of Saliva
Carbamazepine Concentrations After Treatment With Conventional and Slow-Release
Carbamazepine*
area under the AUC * N = 12. =
t
curve.
Mean ± SD.
TABLE 4
Pharmacokinetic Data of Saliva Carbamazepine-10,11-epoxide Concentrations After Treatment With Conventional and Slow-Release Carbamazepine*
AUC area under the curve; NS * N = 12. t Mean ± SD. =
=
not
significant.
161
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
to 41.3 nmol/mL
during treatment with slow-release carbamazepine and from 13.9 to 63.4 nmol/mL with conventional carbamazepine; the corresponding carbamazepine-10,11-epoxide plasma levels were 1.4 to 10.6 nmol/mL and 2.1 to 14.2 nmol/mL, respectively. The mean diurnal plasma and saliva concentration profiles on treatment with conventional and slow-release carbamazepine, respectively, are illustrated in Figures 1 and 2, and a good correlation between the profiles is also seen. Although the mean concentration profiles on treatment with slow-release carbamazepine showed a marked reduction in fluctuations compared to conventional carbamazepine treatment, interindividual variations among the patients occur, as shown by two examples in Figure 3. The mean fluctuation index of carbamazepine in plasma was significantly lower during treatment with slow-release compared with conventional carbamazepine, the difference being about 35%. The fluctuation indexes for each patient during treatment with the two formulations were ordered into clustered
FIGURE 2 Diurnal mean saliva
and carbamaconcentration profiles in 12 children with epilepsy on treatment with conventional carbamazepine (C, 8-8-8) and carbamazepine slow-release
zepine-10,11-epoxide (CBZ-E) formulation (SR,
range-classes (Figure 4). Clinical Judgmentt There were no differences in the seizure control between the two treatment periods. Twelve patients were seizure free on both preparations, and five had the same seizure frequency. Six children had a
carbamazepine (CBZ)
0-0-0).
decreased and two an increased seizure frequency on treatment with slow-release carbamazepine. A total of 18 patients reported 28 side effects usually described during treatment with conventional carbamazepine, the most common being fatigue (n = 10) followed by aggressive behavior (n = 3) and somnolence (n 3). During treatment with slowrelease carbamazepine, four patients reported the following single, mild side effects: gastralgia, diarrhea, cephalalgia, and nausea. In addition, one patient reported skin eruption lasting for a few hours on the second day of treatment, two reported less tiredness than before, and another patient reported concentration problems, hyperactivity, and affect lability. The global evaluation of efficacy and tolerability made by both the patients and the physicians was a clear-cut preference for slow-release carbamazepine. Twenty-four children preferred the slow-release form and one child had no preference. Eighty percent of the physicians preferred slow-release carbamazepine and 20% had no preference. =
Follow-up FIGURE 1 Diurnal mean
plasma carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) concentration profiles in 21
epilepsy on treatment with conventional carbamazepine (C, 0-0-0) and carbamazepine slow-release children with
formulation
(SR, 0-0-0).
Of the initial 25 patients included in the study, all remained on slow-release carbamazepine after 1 year or more (range, 52 to 92 weeks). Eight had been seizure free, while nine experienced a decrease and six an increase in seizure frequency compared with the initial test period (data missing on two). The dose
162
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
Discussion In our study sample of children with epilepsy who were first treated with conventional carbamazepine for 4 weeks and then with the slow-release form for another 4 weeks, the diurnal fluctuation of carbamazepine in plasma was significantly reduced with the slow-release formulation. The reduction of the diurnal fluctuation of carbamazepine in plasma seems to be more pronounced in children than in adults. Our study shows a mean fluctuation index of 0.60 on treatment with conventional carbamazepine and 0.39
FIGURE 3 Diurnal plasma
carbamazepine (CBZ) and carbamazepine10,11-epoxide (CBZ-E) concentration profiles in individual children with epilepsy on treatment with conventional carbamazepine (C, 8-8-8) and carbamazepine slow-release formulation (SR, 0-0-0). A. A 4-year-old boy showing a dramatic reduction in diurnal fluctuation. B. An 8-year-old boy with small diurnal fluctuation differences.
in eight patients; five got a higher and lower dose. In one patient, treatment was discontinued. Of the five with an increased dose, four had had one or more seizures on the original dose, but after dose correction they returned to their former seizure frequency. was
changed
three
a
FIGURE 4 The fluctuation index
classes, during
(FI) for each patient, clustered into FI
treatment with
conventional
carbamazepine
(A) and carbamazepine slow-release formulation (B). Lower FI values for slow-release tablets indicate less fluctuation. ,
163
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
with slow-release carbamazepine, which is a 35% decrease. This should be compared with the fluctuation indexes in adults of 0.28 and 0.21, respectively, 11 a decrease of 25%. The difference between children and adults is most probably explained by the more rapid rate of metabolism in children compared with
adults. 1 . Individual children who
displayed
a
great fluc-
tuation, with high peak concentration levels of reduction in Cmax the slow-release formulation, making the fluctuation profile almost flat. In contrast, a few patients with less pronounced fluctuations on conventional carbamazepine treatment did not benefit so much from the slow-release tablets, as judged by the diurnal plasma concentration curve. The mean Cmax was also significantly decrease (26%) with slowrelease carbamazepine. No significant difference was detected in mean Cmin of carbamazepine in plasma between the two formulations. The mean relative bioavailability (24-hr AUC) was about 22% lower with slow-release than with conventional carbamazepine. This is in agreement with previous results from adult patients. 11,13-15 The importance of a lowered bioavailability of the slowrelease formulation must be considered when evaluating the clinical effect. A few children in our sample had an increased seizure frequency on followup, which was again reduced with a dose increase. This indicates that the lower bioavailability of slowrelease carbamazepine, together with the increased age, must be taken into account when adjusting
carbamazepine, got a pronounced on
treatment with
dosages. The concentration profile of carbamazepine-10, did not show any significant difference between the two formulations with respect to fluctuation index, and this is also in agreement with data from adult patients When patients were treated with conventional carbamazepine, the average peak plasma concentration in saliva was about 27% that in plasma. The morning fasting values were also on the same order. Our results correspond well with previous results from saliva measurements in children. 9,16 A comparison of mean Cmax in plasma versus saliva on treatment with the slow-release formulation shows that the carbamazepine concentration in saliva is about 27% that in plasma. With regard to Cmim salivary levels are about one-quarter plasma levels. Since the diurnal saliva concentration profile follows the one obtained in plasma, saliva measurements may be appropriate to use when blood samples are difficult to obtain. Saliva sampling is a convenient,
11-epoxide
noninvasive, and painless method, and samples
can
easily be
collected at home. Intermittent side effects and interdosage plasma concentration peaks of carbamazepine are related. 4,7,8 Children may be especially sensitive to high peak plasma concentrations,2 and the side effects may interfere with school work’ and the performance of cognitive tests. 5,17 Our results indicate a beneficial effect on tolerability of the slow-release in comparison with conventional carbamazepine. Quite a number of children reported a sense of fatigue on conventional carbamazepine, whereas only one patient complained of tiredness on slow-release carbamazepine. This might be a consequence of less
pronounced plasma
concentration
peaks.
Anecdotal
information from teachers and parents further strengthen the validity of these reports. However, a verification of these findings by objective measurements is necessary before any definite conclusions can be drawn. In conclusion, this study shows that twice daily administration of slow-release carbamazepine significantly reduces the diurnal fluctuation of carbamazepine plasma and saliva concentrations compared to treatment with the conventional form. The tolerability seems to improve on slow-release carbamazepine, and further studies on, for example, cognitive effects would be clinically useful, especially in children.
Acknowledgments Our thanks are due to Laboratory engineer Gunilla Dahistr6m, Department of Clinical Pharmacology, Faculty of Health Sciences, Linkbping, Sweden, who carried out all plasma concentration measurements.
References 1. Porter
2.
3.
4.
5.
General principles. Clinical efficacy and use of antiepileptic drugs. In Woodbury DM, Penry JK, Pippenger CE (eds): Antiepileptic Drugs. New York, Raven Press, 1982, pp 167-175. Blennow G: Adverse effects from the circadian fluctuations of carbamazepine plasma levels. Acta Paediatr Scand 1983;72: 397-401. Paxton JW, Aman MG, Werry JS: Fluctuations in salivary carbamazepine and carbamazepine-10,11-epoxide concentrations during the day in epileptic children. Epilepsia 1983;24: 716-724. Riva R, Albani F, Ambrosetto G, et al: Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side effects. Epilepsia 1984;25: 476-481. Aldenkamp AP, Alpherts WCJ, Moerland MC, et al: Controlled release carbamazepine: Cognitive side effects in patients with epilepsy. Epilepsia 1987;28:507-514.
RJ:
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6.
Aldenkamp
7.
8.
Alpherts WCJ, Meinardi H, Stores G (eds): Epilepsy. Modern Approaches to the Diagnosis and Multi-handicapped Children. Amsterdam, Lisse
AP,
Education and Instruction of
Publishing, 1987, p 146. Höppener RJ, Kyuer A, Meijer JWA, Hulsman J: Correlation between daily fluctuations of carbamazepine serum levels and intermittent side effects. Epilepsia 1980;21:341-350. Tomson T: Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Arch Neurol
1984;41:830-834. 9. Bäckman E, Dahlström G, Eeg-Olofsson O, Bertler Å: The 24 hour variation of salivary carbamazepine and carbamazepine 10,11-epoxide concentrations in children with epilepsy. Pediatr Neurol 1987;3:327-330. 10. Eichelbaum M, Ekbom K, Bertilsson, L, et al: Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Eur J Clin Pharmacol 1975;8:337-341. 11. Tomson T, Ekberg R, Kihlstrand S, et al: Reduced diurnal fluctuations in carbamazepine plasma concentration by the use of a slow-release formulation. J Epilepsy 1989;2:97-101. 12. Battino D, Bossi L, Croci D, et al: Carbamazepine plasma levels in children and adults: Influence of age, dose, and associated
Drug Monit 1980;2:315-322. Besser R, Katzmann K, Theisohn M: Carbamaretard in der Epilepsietherapie. Akt Neurol 1985;12:70-74.
therapy. 13. Krämer
zepin
Ther
G,
14. Eichelbaum M, von Ulrich GE, Hoffmann F: Pharmakokinetik des Tegretol retard. In Krämer G, Hopf C (eds): Carbamazepin in der Neurologie. Stuttgart, Georg Thieme Verlag, 1987, pp 222-224. 15. Johannessen SI, Henriksen O: Comparison of the serum concentration profiles of Tegretol and two new slow-release preparations. In Wolf P, Dam M, Janz D, Dreyfuss FE (eds): Advances in Epileptology, vol 16. New York, Raven Press, 1987, pp 421-424. 16. Eeg-Olofsson O, Bertler A, Tjärnlund U: Carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva of epileptic children and young adults. In Akimoto H, Kazamatsurin H, Seino M, Ward A (eds): Advances in Epileptology: XIIIth Epilepsy International Symposium. New York, Raven Press, 1982, pp
289-292.
CA, Thompson PJ: Anticonvulsant drugs cognitive function: An update. In Dam M, et al (eds): Epilepsy: Progress in Treatment. New York, John Wiley, 1987,
17. Trimble MR, Cull
and
pp 137-149.
Vignette. Dupuytren’s Lacune When single nervous tracts are paralysed, we very rarely have an opportunity of demonstrating a circumscribed lesion in the brain. For this reason, as well as on account of the character of the individual affected, the following case is not without interest. In the year 1834, while delivering a clinical lecture, Dupuytren was attacked with paralysis of the left facial nerve, and he had the courage to continue his discourse while he supported the left angle of the mouth with his finger. He had already on a previous occasion had a slight attack of vertigo, which subsequently returned during a journey in Italy. The left ala nasi continued collapsed until his death in 1835. His friend Cruveilhier, who examined the head after death, found a light yellow cicatrix on the inner surface of the right lateral ventricle behind the thalamus opticus, at the entrance to the posterior horn. A small cavity
with brownish cellular tissue was found in the right corpus striatum, and another one of the same kind in the grey centre of the left corpus striatum. This case also serves to confirm the fact, that a lesion confined to the grey substance is not followed by a loss of motility, as, with the exception of the one-sided facial paralysis, which is accounted for by the cicatrix in the opposite lateral ventricle, Dupuytren never suffered from any other paralytic affection.
, filled
Excerpted
from
Romberg’s
Manual
Man, Volume 2, translated by E.H. Society, London, 1853, pp 426-427.
of the Nervous Diseases of Sieveking. The Sydenham
165
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
Eeg-Olofsson, MD, PhD;
Heimo L.
Jan Arvidsson, MD; Per-Åke Grahn, MD;
Nilsson, PhD; Bernt Tonnby, MD; Hans
Gylje, MD;
Christer Larsson, MD;
Lars Norén, MD
Abstract overcome the problems of interdosage fluctuations of body fluid concentrations of carbamazepine, a slow-release formulation has been developed. In an open, controlled, within-patient study, the diurnal plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 25 epileptic children first treated with conventional carbamazepine tablets (Tegretol) and then with the Tegretol slow-release preparation. The diurnal plasma concentration curves during treatment with the slow-release formulation showed significantly less variation over 24 hours than during treatment with the ordinary preparation, as measured by the fluctuation index. Mean concentration values also differed significantly, which is explained by a somewhat reduced bioavailability (22% less) of the slow-release formulation. There were no differences in efficacy and tolerability between the two formulations, but there was a clear-cut reduction of reported side effects, especially tiredness, on treatment with the slow-release formulation. For that reason, the slow-release formulation should be a major advantage in treating children with epilepsy, in order to avoid interference with cognitive functions. In 12 children, simultaneous measurements of the concentration of carbamazepine and its epoxide in saliva were made and compared with the plasma values. As expected, the concentration curves corresponded, indicating that saliva sampling is an appropriate alternative for monitoring the concentration of carbamazepine. All children remained on the slow-release J Child Neurol 1990;5:159-165). preparation after the trial and were followed up for 12 months or more. (
In order to
several years, carbamazepine has been as an effective antiepileptic drug in the treatment of both partial and generalized tonic-clonic seizures. Usually, a regimen of a twice daily drug intake has been preferred. However, the usefulness
or
Fused
Received May 23, 1989. Received revised August 16, 1989. for publication Sept 7, 1989. From the Department of Pediatrics (Dr Eeg-Olofsson), Faculty of Health Sciences, Linköping, CIBA-GEIGY AB (Dr Nilsson), Pharmaceuticals Division, Gothenburg, and the Departments of Pediatrics, Central Hospitals of Halmstad (Dr Tonnby), Jönköping (Dr Arvidsson), Vänersborg (Dr Grahn), Västerås (Dr Gylje, Dr Norén), and Skävde (Dr Larsson), Sweden. Address correspondence to Dr Eeg-Olofsson, The National Center for Epilepsy, PO Box 900, N-1301 Sandvika, Norway.
Accepted
of the
drug is influenced by diurnal fluctuations in the plasma levels, leading to transitory side effects in some individuals. This has been noticed especially in &dquo;
adults .5- To avoid this the dividing daily intake into three, or more doses has been tried. 7 This type of four, is and sometimes unreliable, and regimen impractical there is a risk of noncompliance. A slow-release formulation of carbamazepine should produce less fluctuation in the plasma level on twice daily administration. The aim of the present study is to compare the variation over 24 hours of the plasma and saliva concentrations of carbamazepine and its 10,11-epoxide in children on treatment with children 2-’ but also
in
inconvenience,
159
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
conventional carbamazepine tablets and a slow-release
preparation. Material and Methods Twenty-five children, 12 girls and 13 boys whose ages
ranged from 4 to 13 years, were included in this multicenter study in which six different Swedish pediatric departments participated. Aside from their seizure disorder, no other Informed consent for participation was received from the parents. All children were initially treated with conventional carbamazepine (Tegretol tablets 200 mg and 400 mg, CIBA-GEIGY AG) for partial or generalized tonic-clonic seizures ranging from 4 months to 10 years (median, 4.0 yr) in duration. The drug was given twice daily, at approximately 8:00 AM and 8:00 PM, and the dosage ranged from 10.0 to 35.3 mg/kg (mean, 19.1; SD, 7.5 mg/kg). Four patients were protocol violators with regard to pharmacokinetic data: two children were treated with phenobarbital and two children with acetazolamide in addition to carbamazepine. No other concomitant treatment was given. Thus, the kinetic calculations were made on data from 21 children on monotherapy, 10 girls and 11 boys aged 4 to 13 years (mean, 7.5; SD, 2.6 yr). Clinical judgments and tolerability results, however, are based on all 25 children, because we wanted to know if the slow-release preparation could influence these variables irrespectively of mono- or chronic
or
acute disease existed.
polytherapy.
Study Design design was an open, within-patient trial. The study sample was not randomly selected and therefore was subject to unknown biases. However, it is not expected that such a bias should interfere with the results of a pharmacokinetic study. All children had been treated with conventional carbamazepine for at least 4 months before the start of the trial. The patients were followed through a baseline period of 4 weeks with their present dose on a twice daily dose regimen (study period 1). Conventional carbamazepine was then shifted dose by dose to slow-release carbamazepine (Tegretol Retard tablets 200 mg, CIBA-GEIGY AG), and the patients were followed for another 4 weeks (study period 2). At the end of study periods 1 and 2 the children were hospitalized, and 24-hour profiles of the plasma (n 21) and saliva (n = 12) concentrations were taken. Samples were drawn before the morning dose was given at approximately 8:00 AM and then at one-hour intervals until 10:00 PM. Thereafter, samples were obtained The trial
=
AM. Blood and saliva were drawn In order to collect saliva, the child first had to rinse her or his mouth with fresh water. The secretion of saliva was then stimulated by chewing on Parafilm or a plastic tube. About 2 mL of saliva was collected in a glass tube.’ Blood and saliva samples were centrifuged, and the supernatant stored at -20°C. All samples from one center were analyzed at the same time. The concentrations of carbamazepine and its epoxide were assayed by a modified high-performance liquid chromatography method (G. Dahlstrbm and B. Norlander, personal communication) based on the method of Eichelbaum et al.’° Laboratory tests, including a complete blood count and liver function tests (transaminases and alkaline phosphatase), were checked at the start of both study periods.
at
2:00, 6:00, and 8:00
simultaneously.
Clinical Assessment: Efficacy and Tolerability The change in seizure frequency was recorded at the end of each study period and the overall efficacy rated on a 5-point scale (much worse, worse, same, better, much better). A general assessment of the tolerability with the scale
performed after study period 2. At the same preference for the conventional or slow-release form of the drug was obtained from the patient and parents, as well as from the treating doctor. The nature, date of onset, severity (mild not disturbing, moderate disturbing but acceptable, severe markedly disturbing), frequency, duration, and relation to treatment of any symptom observed by the medical staff or reported by the same
was
time, information about
=
=
=
parents
were
recorded.
Calculations and Statistics The
systemic relative bioavailability over 24 hours obtained by calculating the areas under the plasma concentration-time curve (24-hr AUC); the calculations were carried out by the trapezoidal rule. To achieve comparable values in one case where the 0-hour value was missing, this value was substituted by the respective 24-hour value. The same procedure was performed in 2 cases in which the 24-hour value was missing. The mean diurnal plasma concentrations were calculated as the mean peak concentrations (Cmax) and the mean lowest concentration over 24 hours (Cmin)’ To be able to compare the plasma concentration-time profiles on treatment with conventional and slow-release carbamazepine, a fluctuation index (FI) was calculated by the following formula: was
FI
Cmax Cumin
= 24-hr AUC 24
Since the number of
patients from each
center
was
low,
no
homogeneity analysis was conducted. The Student’s t-test was used for significance tests. Since no control group was present, significance tests were not used in connection with the clinical assessments.
Results Pharmacokinetics The pharmacokinetic calculations of carbamazepine and its main metabolite, the 10,11-epoxide, in plasma after treatment with conventional and slow-release formulations, respectively, are shown in Tables 1 and 2, and calculations for salivary values in Tables 3 and 4. The 24-hr AUC values of slow-release compared to conventional carbamazepine were about 22% lower (data from plasma). Treatment with slow-release carbamazepine twice daily leads to a significant reduction of mean Cmax by about 26% compared to treatment with conventional carbamazepine, and no
significant difference was seen in mean Cumin. Carbamazepine plasma levels ranged from
160
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015
11.2
TABLE 1
Carbamazepine Concentrations After Treatment With Conventional and Slow-Release
Pharmacokinetic Data of Plasma
Carbamazepine*
AUC area under the curve; NS * N = 21. =
t
=
significant.
Mean ± SD.
TABLE 2 Pharmacokinetic Data of Plasma Slow-Release Carbamazepine*
area under the AUC * N = 21. =
t
not
curve;
NS
Carbamazepine-10,11-epoxide Concentrations After
=
not
Treatment With Conventional and
significant.
’
>
Mean ± SD. ’
TABLE 3 Pharmacokinetic Data of Saliva
Carbamazepine Concentrations After Treatment With Conventional and Slow-Release
Carbamazepine*
area under the AUC * N = 12. =
t
curve.
Mean ± SD.
TABLE 4
Pharmacokinetic Data of Saliva Carbamazepine-10,11-epoxide Concentrations After Treatment With Conventional and Slow-Release Carbamazepine*
AUC area under the curve; NS * N = 12. t Mean ± SD. =
=
not
significant.
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to 41.3 nmol/mL
during treatment with slow-release carbamazepine and from 13.9 to 63.4 nmol/mL with conventional carbamazepine; the corresponding carbamazepine-10,11-epoxide plasma levels were 1.4 to 10.6 nmol/mL and 2.1 to 14.2 nmol/mL, respectively. The mean diurnal plasma and saliva concentration profiles on treatment with conventional and slow-release carbamazepine, respectively, are illustrated in Figures 1 and 2, and a good correlation between the profiles is also seen. Although the mean concentration profiles on treatment with slow-release carbamazepine showed a marked reduction in fluctuations compared to conventional carbamazepine treatment, interindividual variations among the patients occur, as shown by two examples in Figure 3. The mean fluctuation index of carbamazepine in plasma was significantly lower during treatment with slow-release compared with conventional carbamazepine, the difference being about 35%. The fluctuation indexes for each patient during treatment with the two formulations were ordered into clustered
FIGURE 2 Diurnal mean saliva
and carbamaconcentration profiles in 12 children with epilepsy on treatment with conventional carbamazepine (C, 8-8-8) and carbamazepine slow-release
zepine-10,11-epoxide (CBZ-E) formulation (SR,
range-classes (Figure 4). Clinical Judgmentt There were no differences in the seizure control between the two treatment periods. Twelve patients were seizure free on both preparations, and five had the same seizure frequency. Six children had a
carbamazepine (CBZ)
0-0-0).
decreased and two an increased seizure frequency on treatment with slow-release carbamazepine. A total of 18 patients reported 28 side effects usually described during treatment with conventional carbamazepine, the most common being fatigue (n = 10) followed by aggressive behavior (n = 3) and somnolence (n 3). During treatment with slowrelease carbamazepine, four patients reported the following single, mild side effects: gastralgia, diarrhea, cephalalgia, and nausea. In addition, one patient reported skin eruption lasting for a few hours on the second day of treatment, two reported less tiredness than before, and another patient reported concentration problems, hyperactivity, and affect lability. The global evaluation of efficacy and tolerability made by both the patients and the physicians was a clear-cut preference for slow-release carbamazepine. Twenty-four children preferred the slow-release form and one child had no preference. Eighty percent of the physicians preferred slow-release carbamazepine and 20% had no preference. =
Follow-up FIGURE 1 Diurnal mean
plasma carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) concentration profiles in 21
epilepsy on treatment with conventional carbamazepine (C, 0-0-0) and carbamazepine slow-release children with
formulation
(SR, 0-0-0).
Of the initial 25 patients included in the study, all remained on slow-release carbamazepine after 1 year or more (range, 52 to 92 weeks). Eight had been seizure free, while nine experienced a decrease and six an increase in seizure frequency compared with the initial test period (data missing on two). The dose
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Discussion In our study sample of children with epilepsy who were first treated with conventional carbamazepine for 4 weeks and then with the slow-release form for another 4 weeks, the diurnal fluctuation of carbamazepine in plasma was significantly reduced with the slow-release formulation. The reduction of the diurnal fluctuation of carbamazepine in plasma seems to be more pronounced in children than in adults. Our study shows a mean fluctuation index of 0.60 on treatment with conventional carbamazepine and 0.39
FIGURE 3 Diurnal plasma
carbamazepine (CBZ) and carbamazepine10,11-epoxide (CBZ-E) concentration profiles in individual children with epilepsy on treatment with conventional carbamazepine (C, 8-8-8) and carbamazepine slow-release formulation (SR, 0-0-0). A. A 4-year-old boy showing a dramatic reduction in diurnal fluctuation. B. An 8-year-old boy with small diurnal fluctuation differences.
in eight patients; five got a higher and lower dose. In one patient, treatment was discontinued. Of the five with an increased dose, four had had one or more seizures on the original dose, but after dose correction they returned to their former seizure frequency. was
changed
three
a
FIGURE 4 The fluctuation index
classes, during
(FI) for each patient, clustered into FI
treatment with
conventional
carbamazepine
(A) and carbamazepine slow-release formulation (B). Lower FI values for slow-release tablets indicate less fluctuation. ,
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with slow-release carbamazepine, which is a 35% decrease. This should be compared with the fluctuation indexes in adults of 0.28 and 0.21, respectively, 11 a decrease of 25%. The difference between children and adults is most probably explained by the more rapid rate of metabolism in children compared with
adults. 1 . Individual children who
displayed
a
great fluc-
tuation, with high peak concentration levels of reduction in Cmax the slow-release formulation, making the fluctuation profile almost flat. In contrast, a few patients with less pronounced fluctuations on conventional carbamazepine treatment did not benefit so much from the slow-release tablets, as judged by the diurnal plasma concentration curve. The mean Cmax was also significantly decrease (26%) with slowrelease carbamazepine. No significant difference was detected in mean Cmin of carbamazepine in plasma between the two formulations. The mean relative bioavailability (24-hr AUC) was about 22% lower with slow-release than with conventional carbamazepine. This is in agreement with previous results from adult patients. 11,13-15 The importance of a lowered bioavailability of the slowrelease formulation must be considered when evaluating the clinical effect. A few children in our sample had an increased seizure frequency on followup, which was again reduced with a dose increase. This indicates that the lower bioavailability of slowrelease carbamazepine, together with the increased age, must be taken into account when adjusting
carbamazepine, got a pronounced on
treatment with
dosages. The concentration profile of carbamazepine-10, did not show any significant difference between the two formulations with respect to fluctuation index, and this is also in agreement with data from adult patients When patients were treated with conventional carbamazepine, the average peak plasma concentration in saliva was about 27% that in plasma. The morning fasting values were also on the same order. Our results correspond well with previous results from saliva measurements in children. 9,16 A comparison of mean Cmax in plasma versus saliva on treatment with the slow-release formulation shows that the carbamazepine concentration in saliva is about 27% that in plasma. With regard to Cmim salivary levels are about one-quarter plasma levels. Since the diurnal saliva concentration profile follows the one obtained in plasma, saliva measurements may be appropriate to use when blood samples are difficult to obtain. Saliva sampling is a convenient,
11-epoxide
noninvasive, and painless method, and samples
can
easily be
collected at home. Intermittent side effects and interdosage plasma concentration peaks of carbamazepine are related. 4,7,8 Children may be especially sensitive to high peak plasma concentrations,2 and the side effects may interfere with school work’ and the performance of cognitive tests. 5,17 Our results indicate a beneficial effect on tolerability of the slow-release in comparison with conventional carbamazepine. Quite a number of children reported a sense of fatigue on conventional carbamazepine, whereas only one patient complained of tiredness on slow-release carbamazepine. This might be a consequence of less
pronounced plasma
concentration
peaks.
Anecdotal
information from teachers and parents further strengthen the validity of these reports. However, a verification of these findings by objective measurements is necessary before any definite conclusions can be drawn. In conclusion, this study shows that twice daily administration of slow-release carbamazepine significantly reduces the diurnal fluctuation of carbamazepine plasma and saliva concentrations compared to treatment with the conventional form. The tolerability seems to improve on slow-release carbamazepine, and further studies on, for example, cognitive effects would be clinically useful, especially in children.
Acknowledgments Our thanks are due to Laboratory engineer Gunilla Dahistr6m, Department of Clinical Pharmacology, Faculty of Health Sciences, Linkbping, Sweden, who carried out all plasma concentration measurements.
References 1. Porter
2.
3.
4.
5.
General principles. Clinical efficacy and use of antiepileptic drugs. In Woodbury DM, Penry JK, Pippenger CE (eds): Antiepileptic Drugs. New York, Raven Press, 1982, pp 167-175. Blennow G: Adverse effects from the circadian fluctuations of carbamazepine plasma levels. Acta Paediatr Scand 1983;72: 397-401. Paxton JW, Aman MG, Werry JS: Fluctuations in salivary carbamazepine and carbamazepine-10,11-epoxide concentrations during the day in epileptic children. Epilepsia 1983;24: 716-724. Riva R, Albani F, Ambrosetto G, et al: Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side effects. Epilepsia 1984;25: 476-481. Aldenkamp AP, Alpherts WCJ, Moerland MC, et al: Controlled release carbamazepine: Cognitive side effects in patients with epilepsy. Epilepsia 1987;28:507-514.
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Alpherts WCJ, Meinardi H, Stores G (eds): Epilepsy. Modern Approaches to the Diagnosis and Multi-handicapped Children. Amsterdam, Lisse
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Publishing, 1987, p 146. Höppener RJ, Kyuer A, Meijer JWA, Hulsman J: Correlation between daily fluctuations of carbamazepine serum levels and intermittent side effects. Epilepsia 1980;21:341-350. Tomson T: Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Arch Neurol
1984;41:830-834. 9. Bäckman E, Dahlström G, Eeg-Olofsson O, Bertler Å: The 24 hour variation of salivary carbamazepine and carbamazepine 10,11-epoxide concentrations in children with epilepsy. Pediatr Neurol 1987;3:327-330. 10. Eichelbaum M, Ekbom K, Bertilsson, L, et al: Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Eur J Clin Pharmacol 1975;8:337-341. 11. Tomson T, Ekberg R, Kihlstrand S, et al: Reduced diurnal fluctuations in carbamazepine plasma concentration by the use of a slow-release formulation. J Epilepsy 1989;2:97-101. 12. Battino D, Bossi L, Croci D, et al: Carbamazepine plasma levels in children and adults: Influence of age, dose, and associated
Drug Monit 1980;2:315-322. Besser R, Katzmann K, Theisohn M: Carbamaretard in der Epilepsietherapie. Akt Neurol 1985;12:70-74.
therapy. 13. Krämer
zepin
Ther
G,
14. Eichelbaum M, von Ulrich GE, Hoffmann F: Pharmakokinetik des Tegretol retard. In Krämer G, Hopf C (eds): Carbamazepin in der Neurologie. Stuttgart, Georg Thieme Verlag, 1987, pp 222-224. 15. Johannessen SI, Henriksen O: Comparison of the serum concentration profiles of Tegretol and two new slow-release preparations. In Wolf P, Dam M, Janz D, Dreyfuss FE (eds): Advances in Epileptology, vol 16. New York, Raven Press, 1987, pp 421-424. 16. Eeg-Olofsson O, Bertler A, Tjärnlund U: Carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva of epileptic children and young adults. In Akimoto H, Kazamatsurin H, Seino M, Ward A (eds): Advances in Epileptology: XIIIth Epilepsy International Symposium. New York, Raven Press, 1982, pp
289-292.
CA, Thompson PJ: Anticonvulsant drugs cognitive function: An update. In Dam M, et al (eds): Epilepsy: Progress in Treatment. New York, John Wiley, 1987,
17. Trimble MR, Cull
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Vignette. Dupuytren’s Lacune When single nervous tracts are paralysed, we very rarely have an opportunity of demonstrating a circumscribed lesion in the brain. For this reason, as well as on account of the character of the individual affected, the following case is not without interest. In the year 1834, while delivering a clinical lecture, Dupuytren was attacked with paralysis of the left facial nerve, and he had the courage to continue his discourse while he supported the left angle of the mouth with his finger. He had already on a previous occasion had a slight attack of vertigo, which subsequently returned during a journey in Italy. The left ala nasi continued collapsed until his death in 1835. His friend Cruveilhier, who examined the head after death, found a light yellow cicatrix on the inner surface of the right lateral ventricle behind the thalamus opticus, at the entrance to the posterior horn. A small cavity
with brownish cellular tissue was found in the right corpus striatum, and another one of the same kind in the grey centre of the left corpus striatum. This case also serves to confirm the fact, that a lesion confined to the grey substance is not followed by a loss of motility, as, with the exception of the one-sided facial paralysis, which is accounted for by the cicatrix in the opposite lateral ventricle, Dupuytren never suffered from any other paralytic affection.
, filled
Excerpted
from
Romberg’s
Manual
Man, Volume 2, translated by E.H. Society, London, 1853, pp 426-427.
of the Nervous Diseases of Sieveking. The Sydenham
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