Reduction of dosing frequency of carbamazepine with a slow-release preparation

Epilepsy Res.,

32

2 ( 1988) 32-36 Elsevier

ERS 00163

Reduction of dosing frequency of carbamazepine with a slow-release preparation

J. Sivenius”, E. Heinonenb, H. Lehtob, P. JWxmsivu”, M. Anttilab, A. Ylinend and P. Riekkinen” “Department of Neurology, Turku (Finland),

University Central Hospital of Kuopio, Kuopio (Finland), ‘Medipolar,

bResearch Center, Farmos Group Ltd.,

Farmos Group Ltd., Zulu (Finland), and dVaajasalo Epilepsy Hospital, Kuopio (Finland)

(Received 24 April 1987; revised received and accepted 7 July 1987) Key words: Carbamazepine;

Serum concentration;

Slow release preparation; Epilepsy; Antiepj~ptic

drug

The occurrence of side effects and epileptic seizures and the pharmacokinetics of carbamazepine (CBZ) and carbamazepine-10,l lepoxide were studied using a slow-release CBZ preparation, Neurotol slow, and a conventional CBZ preparation, Tegretol. The study was an open, randomized cross-over trial, with a 2 week study period for each preparation. Tegretol was given 3 times and Neurotol slow twice a day. The earlier CBZ dose was kept unchanged. The initial sample consisted of 24 adult epileptic patients receiving CBZ treatment of whom 20 patients were evaluable. The fluctuation in serum CBZ concentrations did not differ significantly between the 2 treatment periods, even though the interdose interval of Neurotol slow was 4 h longer than that of Tegretol. The switch-over from conventional CBZ to the slow-release formulation did not seem to alter the efficacy and side effects of CBZ. By using Neurotol slow instead of a conventional CBZ preparation, Tegrrtol. it is evidently possibIe to reduce the dosing frequency from 3 times a day to twice daily administrations.

INTRODUCTION Carbamazepine (CBZ) is one of the most important antiepileptic drugs, used specifically in the treatment of partial and secondary generalized epileptic seizures. An important objective in CBZ therapy is the achieving of serum concentrations of the drug of maximum stabihty and clinical effectiveness (4-8 mg/l, 17-40 ~molil). In order to reach this goal the daily CBZ dose is often divided into several doses. Correspondence to: Dr. Juhani Sivenius, Department Neurology, Kuopio University. SF-20101 Kuopio, Finland.

of

The total dose of CBZ often has to be raised as well. All this leads to an increased frequency of side effects of CBZ2*3.9 and thus perhaps to reduced patient compliance. A possible way of achieving a more stable serum CBZ concentration is by using a slow-release preparation. As of now only few clinical studies have been published on slow-release CBZ preparations as compared with conventional ones4_ In a study by Johannessen and Henriksen4 the maximal serum concentration (C,,,) was significantly lower with 2 different slow-release CBZ preparations when compared with a conventional CBZ preparation. Morning trough levels were higher with

0920-12111X8/$03.500 1988 Elsevier Science Publishers B.V. (Biomedical Division)

33 both slow-release preparations, but the mean daily concentrations were lower. In a Finnish studyX the fluctuations of the serum CBZ concentration were significantly lower (P < 0.001) with Neurotol slow than with a conventional preparation (Tegretol). Most of the patients in these studies were on poIytherapy. The purpose of the present study was to determine whether a slow-release CBZ preparation administered twice a day functions pharmacokinetitally as well as a conventional CBZ preparation given 3 times a day. The degree of fluctuation of serum CBZ and carbamazepine-lO,ll-epoxide (CBZE) concentrations, control of seizures and side effects were monitored under steady-state conditions.

dose) at the beginning of the study, 1 week after the beginning of each period and at the beginning of each blood sample series. This series of blood samples was taken at the end of each 2 week study period and consisted of blood samples taken at intervals of 2 h after the administration of the morning dose of CBZ (up to 8.00 p.m.). During the study periods the occurrence of epileptic seizures and side effects was recorded. Special attention was paid to the occurrence of dizziness, fatigue and disturbances of vision. The patients were also asked which study period they preferred. Serum CBZ and CBZE concentrations were determined by an HPLC method’.

PATIENTS AND METHODS

Pharmacokinetic parameters were calculated from serum CBZ and CBZE as follows: C,,, was determined as the highest observed concentration during the first interdose interval: t,,, was determined as the time at which C,,, occurred during the first interdose interval. When adjacent concentrations were equal to C,,, the median time was taken as t,,,. Cmj, was taken as the iowest observed concentration during the first interdose interval. AD,,, was defined as the deviation of determined concentrations from C””(the areas above and below (C,,) and was determined by the trapezoidal rule. cSs was the time-averaged concentration at steady state and was determined by the AUC D_12 ,, divided by the study interval (12 h).

Patients

The study was performed at the Kuopio University Central Hospital in 19851986. Adult epileptic patients with CBZ monotherapy whose CBZ therapy had been stable and on a therapeutic dose level for at least 6 months were eligible for the study. Patients with a severe somatic or psychiatric disease or gravidity were excluded from the study. Drugs

The following commercially available carbamazepine products were used in the study: NeurotolO slow (Neurotol slow) 200 mg tablet (Laakefarmos/Farmos Group Ltd.) and Tegretol@ (Tegretol) 200 mg tablet (Ciba-Geigy). Study design

The study was an open, randomized cross-over study. The patients were randomized to receive either Tegretol or Neurotol slow. The daily CBZ dose was divided into 3 doses during the Tegretol and into 2 doses during the Neurotol slow period, which were of 2 weeks duration each. The mean daily CBZ dose was to be maintained the same as before the study. The drugs were given in identical containers. The serum CBZ and CBZE concentrations were measured from the morning samples (taken at 8.00 a.m. before the administration of the morning

Statistical analysis

The statistical comparisons of the pharmacokinetic parameters of CBZ and CBZE were performed using an analysis of variance for repeated measurements, extracting effects due to sequence, period and treatment. t,,, values were compared by the Wilcoxon signed rank test. RESULTS Pharmacokinetic

results

Altogether 24 patients started the study. Four patients had to be excluded, two due to poor compliance, one due to protocol violation and one due to difficulties in the HPLC analysis. The charac-

34 TABLE I Characteristics of the 20

evaluablepatients in the study Mean (range) 36.9 (18-62)

Age (years) Duration of treatment (years) Duration of treatment with CBZ (years) Daily CBZ dose (mg) Division of mean daily CBZ dose (mg) Tegretol Neurotol slow

11.3 (1.2-34) 5.2 (1.2-13.2) 615.0 (300-1100) 230 + 155 + 230 280 + 350

_

0

2

‘

6

9

10 TIM%

teristics of the evaluable patients are presented in Table 1. There were 9 females and 11 males in the study. Three patients were also receiving other than antiepileptic medication: one for asthma, one for arterial hypertension and one for hypothyreosis. During the Tegretol period the mean CBZ dose was administered as follows: 230 mg at 8 a.m., 155 mg at 4 p.m. and 230 mg at 8 p.m. During the Neurotol slow period the mean doses were 280 mg at 8 a.m. and 350 mg at 8 p.m. As the dosing interval, the morning dose and the total CBZ dose during the first 12 h were different in the 2 treatment groups, the AUC values could not be used for the evaluation of bioavailability. The C,,,, Cmin, t,,, and C,,,/C,,, were analyzed from the interdose interval. C,,, was significantly lower (P < 0.01) during the Neurotol slow period (Table II). The time needed to reach the maximum concentration (t,,,) was significantly longer (P < 0.05) during the Neurotol slow period than during the Tegretol period (Fig. 1). Cmin was significantly lower during the

!2

q

~-~

aide,

..__j~~~i

7

‘

lb’

6

R

10 T,MF

12 Ihl

Fig. 1. Steady-state serum concentration of carbamazepine during 12 h interval. Arrows indicate time of administration of carbamazepine doses.

Neurotol slow period. There were no statistically significant differences in the fluctuations (C,,,/ C,,,, AD,,,) of serum CBZ levels during the 12 h between the 2 treatments (Table 11). The Cnl,Xof serum carbamazepine-10,l l-epoxide was higher during the Tegretol period, but the difference was not statistically significant. The Cminof CBZE was significantly lower during Neurotol slow treatment, but C,,,/C,, was lower (P < 0.001) during the Tegretol treatment. The AD,,, of the serum CBZE concentrations (Fig. 2) during 12 h were the same for both drugs (AD,,,, Table III). The CBZ and CBZE concentrations of the morning samples (taken at the beginning of the study, 1 week after the initiation of the study and at the beginning of the blood sample series) did not differ significantly between the 2 treatments (Table IV).

TABLE II Comparative steady-state pharmacokinetics

of carbamazepine:

Neurotol slow 200 mg vs. Tegretol200 mg tablet in 20 epileptic patients

Pharmacokinetic

Neurotol slow (N)

Tegretol (T)

Differences

Statistical significance

parameters

(mean (S. 0.)) ~_~_~

(mean (S. D.))

(Nl T)

(P)

7.04 (1.41) 4.10 (2.47) 5.42(1.01) 1.30 (0.13) 4.89 (2.56)

7.69 (1.36) 2.8 (1.2) 6.06 (0.99) 1.27 (0.07) 5.04 (1.98)

0.92 1.46 0.89 1.02 0.97

0.0068 0.0159 0.0005 0.1217 0.8456

C,,,

&WY

t,,, (h)” C,,, Olg/mUh C,,X’Cnl,“” ADp (&h/ml)b

_~~_~

BValues of parameters calculated from the first interdose interval (Tegretol@ O-8 h, Neurotol@ slow O-12 h). ’ From the whole follow-up time (O-12 h).

35 half-lives

are reduced

tients are treated such as phenytoin,

even

further

when

tal’. This increase in the metabolism zepine results in greater fluctuation drug concentration polytherapy”. carbamazepine Fig.

2. Steady-state

epoxide

during

concentration

12 h interval. tration

associated

of carbamazepine-lO,ll-

Arrows

indicate

of carbamazepine

time of adminis-

if the patients

are on

The occurrence of side effects of treatment has been shown to be

with

fluctuation

in serum

concentra-

tionsY.12. In order to reduce

doses.

values for all patients

were with-

in the normal range. There were 9 epileptic seizures during each of the treatment periods. The most common side effect complaint by the patients was fatigue, occurring in 4 patients in each group. There was practically no difference in side effects between the 2 treatment periods. At the end of the study the patients were also asked which study period they preferred. Ten patients (50%) preferred Neurotol slow, 4 patients (20%) Tegretol and 6 (30%) patients had no preference. DISCUSSION of carbamazepine

is relatively

long,

20-65 h, when administered as a single dose to Owing the autoinduction, healthy volunteers”. however, plasma half-lives decreased to lo-15 h during carbamazepine maintenance therapy6. The

TABLE

especially

of carbamain the serum

the occurrence

of side effects,

the division of the daily dose has been suggested into 3 or 4 dosages”‘.“. This. however, reduces the

Clinical data The laboratory

The half-life

the pa-

with other antiepileptic drugs ethosuximide and phenobarbi-

compliance of the patients. According to our results, administering carbamazepine twice daily with Neurotol slow gave the same fluctuations in serum concentrations of CBZ as when administered 3 times a day with Tegretol. The concentration of CBZ remained well within the therapeutic range. It is especially noteworthy that the morning trough levels were the same with both alternatives. C,,, was significantly lower with Neurotol slow than with Tegretol. These results are in agreement with previous reports’.‘. Our study scheme was pragmatic, based on intention to treat. and resembling normal clinical praxis when dosing is changed from 3 to 2 daily doses or vice versa. In this respect it should be noted that the fluctuation in doses and different dosing schemes (b.i.d./t.i.d.) caused methodological problems and partial limitations to the study. Thus, bioavailability (AUC) could not be assessed, and further comparison of fluctuations in

III

Comparative steady-state pharmacokinetics of carbamazepine-lO,Il-epoxide:

Neurotol slow 200 mg tablet vs. Tegretol200 mg tablet in

20 epileptic patients

tmax could not be calculated

because

of the plateau

form of the carbamazepine-lO,ll-epoxide

curve.

_ Pharmacokinetic

Neurotol slow (N)

Tegretol (T)

Differences

Statistical signtficance

parameters

(mean (S. D.))

(mean (S. 0.))

(Nl Tl

(P) 0.0641

____..

C,,, OcgW”

0.79 (0.27)

0.87 (0.24)

0.91

C,,, Cug/mV

0.59 (0.18)

0.72 (0.19)

0.82

0.0004

Gl&rn,rl” AD,I~ (ugihiml)h ~_

1.34 (0.17)

1.20 (0.07)

1.12

0.0005

0.62 (0.49)

0.61 (0.34)

1.02

0.7003

a The values of these parameters have been calculated ’ From the whole follow-up time (0- 12 h).

from the first interdose

interval

(Tegretol

O-8 h, Neurotol

slow 0- 12 h).

36 TABLE IV Serum concentrations of carbamazepine

and carbamarepine-i0,11-epoxide

in morning samples (before administration of morning

dose) Time point

ofblood

samples

At beginning of study One week after beginning of study period At beginning of blood sample series

CarbamazepinP

Carbamarepine-It&II-epoxide”

Neurotol slow

Tegretol

Neurotol slow

Tegretol

@g~mU

bglml)

@glml)

(fig/ml)

5.98 + 1.08 6.83 * 1.14 6.38 f 1.80

6.87 + 1.26 6.29 + 1.16 6.32 + 1.27

0.71 t 0.21 0.78 + 0.23 0.75 It 0.26

0.80 + 0.21 0.76 t 0.23 0.76 & 0.22

____~.

a Mean & SD.

serum levels could only be performed for interdose intervals, resulting in 8 h and 12 h profiles for CBZ and slow-release CBZ formulations, respectively. Blood samples were not obtained during the night after 8 p.m. The occurrence of side effects and epileptic seizures did not differ between the 2 treatment periods. It is, however, to be stated that the duration of the study as well as the number of patients included were not sufficient to evaluate these aspects in detail. In view of the present pharmacokinetic data, however, it seems to be possible to re-

duce the dosing frequency of CBZ using a slow-release CBZ preparation, Neurotol slow.

ACKNOWLEDGEMENTS We wish to thank the following persons and institutions: Mr. Juhani Tuominen for expert statistical advice, Mrs. Merja Love for accurate computer work, Mrs. Leena Korhonen for the preparation of the manuscript and Farmos Group Ltd. for providing the research material.

REFERENCES Eichelbaum, M., Kbthe, K.W., Hoffmann, F. and Von Unruh, G.E., Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy, C&n. Pharmacol. Ther., 26 (1979) 366-371.

Ghose, K., Fry, D.E. and Christofides, J.A., Effect of dosage frequency of carbamazepine on drug serum levels in epileptic patients, Europ. J. clin. Pharmacol., 24 (1983) 3X-381.

Hiippener, R.J., Kuyer, A., Meijer, J.W.A. and Hulsman, J.. Correlations between daily fluctuations of carbamazepine serum levels and intermittent side effects, Epilepsia, 21(1980) 341-350. Johannessen, S.I. und Henriksen, O., Vergleich det Serumkonzentrations-Profile einer Carbamazepin StandardTablette under zweier Slow-Release-PrHparate. In: J.W.A. Meijer (Ed.), 1st Int. ~arba~ze~in Sio~-Rele~e Symposium, Zuckschwert, Munich, 1986. Jiirgens, U., May, T., HollenkStter, K. and Rambeck, B., Systematic comparison of the basic methods of sample pretreatment for high-performance liquid chromatographic analysis of antiepileptic drugs using gas chromatography as a reference method, Ther. Drug Monit., 6 (1984) 334-343. 6 Morselli, P.L. and Frigerio, A., Metabolism and pharmacokinetics of carbamazepine, Drug. Metab. Rev., 4 (1975) 97-113.

7 Perucca, E., Pharmacokinetic interactions with antiepileptic drugs, Clin. Pharmacokinet., 7 (1982) 57-84. 8 Reunanen, M., Heinonen, E., Lehto, H., Anttila, M. and Hokkanen, E., Pha~acokinetic and cIinica1 comparison of b.i.d. Neurotol* slow 200 rng and Tegretol’ 200 mg tablets in epileptic patients under steady-state conditions. Data on file, Research Center, Farmos Group Ltd., Turku, Finland. 9 Riva, R., Albani, F., Ambrosetto, G., Contin, M., Cortelli, P., Perucca, E. and Baruzzi, A., Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side-effects, Epilepsia, 25 (1984) 476-481.

10 Schneider, H. und Stenzel, E., Carbamazepine: tageszeitlithen Verlauf des Serumspiegels unter Langzeitsmedikation, Bibl. psychiat. (3~el~, 151(1975) 32-42. 11 Strandjord, R.E. and Johannessen, S.I., A preliminary study of serum carbamazepine levels in healthy subjects and in patients with epilepsy. In: H. Schneider et al. (Eds.), Clinical Pharmacology of Anti-Epileptic Drugs, Springer, Berlin, 1975, pp. 181-188. 12 Tomson, T., Interdosage fluctuations in plasma carbamazepine concentration determine inte~ittent side effects, Arch. Neuroi. (Chic.), 41 (1984) 830-833.