Absence of interaction between oxcarbazeDine and ervthromvcin I
J
J
Keranen T, Jolkkonen J, Jensen PK, Menge GP, Andersson P. Absence of interaction between oxcarbazepine and erythromycin. Acta Neurol Scand 1992: 86: 120-123.
T. Keranen', J. Jolkkonen2 P. K. Jensen4, G. P. Menge', P. Andersson
'
When erythromycin (ERY) is co-administrated with the antiepileptic carbamazepine (CBZ), a drug interaction may cause an increase in CBZ plasma concentrations, which can result in CBZ related toxic symptoms. This cross-over study was designated to investigate whether ERY influences the pharmacokinetics of the new antiepileptic oxcarbazepine (OXC) and its metabolites. In 8 healthy volunteers there were no significant differences in AUC, peak plasma concentrations or time to peak concentration when OXC was administered either with or without ERY. The results of this study suggest that OXC may offer an important advantage over CBZ especially when concomitant therapy with ERY is required.
It is well documented in the literature that erythromycin (ERY) causes plasma concentrations of carbamazepine (CBZ) to increase, resulting in CBZ related toxic symptoms such as disturbances of vision, ataxia and dizziness (1). The co-administration of ERY prolongs the elimination half-life of CBZ and reduces its clearance. Serum levels of the metabolite, CBZ-epoxide, are markedly decreased during co-administration of ERY, indicating that the oxidative metabolic pathway is inhibited (2). CBZ is metabolized mainly by oxidative reactions. Repeated administration of CBZ leads to induction of hepatic oxygenases of the cytochrome P450 family. Owing to this auto-induction effect, the total plasma clearance increases in patients during carbamazepine therapy (3,4). Enzyme inducing drugs like phenobarbital or phenytoin can further increase the plasma clearance of CBZ when administered concomitantly. In contrast, enzyme inhibiting drugs like propoxyphene, verapamil or viloxazine counteract the inductive properties of both CBZ and other enzyme inducing drugs (5). Oxcarbazepine (OXC), 10,ll-dihydro - 100x0-5H-dibenz- [b,f] -azepine-5-carboxamide, TriSummary results have been presented at the Annual Meeting of the American Epilepsy Society, San Diego, California, Nov. 11-14, 1990 in Poster Session IV: Antiepileptic Drugs, and were published as in abstract in AES Proceedings in Epilepsia, 31(5): 1990: 641.
120
Department of Pharmacology and Toxicology, University of Kuopio, * Vaajasalo Hospital, Kortejoki, Kuopio, CIBA-GEIGY OY, Helsinki, Finland, Research and Development, Pharmaceuticals Division, CIBA-GEIGY Limited, Basle, Switzerland
Key words: epilepsy; anticonvulsants; erythromycin; drug interactions G.P. Menge, Pharma Research and Development, K-136.2.93. CIBA-GEIGY Limited, CH-4002 Basle, Switzerland Accepted for publication November 29, 1991
leptal@, is a newly introduced anti-epileptic drug which has been shown to be as effective as CBZ in patients suffering from partial seizu'res, with or without secondary generalization, and generalized tonicclonic seizures (6). Although CBZ and OXC are chemically related, their metabolic pathways in man are completely different. In contrast to CBZ, the biotransformation of OXC is controlled mainly by non-inducible hepatic cytosolic reductases (7, 8). In humans OXC is rapidly and almost completely reduced to the antiepileptically active monohydroxy derivative (MHD), 10,ll-dihydro- lO-hydroxy-5H-dibenz-[b,f]azepine-5-carboxamide, which is thought to be mainly responsible for the anti-epileptic effect of OXC. After single oral dose administration, 80 % of an OXC dose is eliminated as MHD and its glucuronide conjugate in the urine. A small amount of MHD is further transformed to the pharmacologically inactive dihydroxy derivative (DHD), 10,lldihydro- lo-, 1l-dihydroxy-5H-dibenz-[b,f]-azepineScarboxamide (9). Unlike CBZ, OXC does not induce enzymes that increase the rate of its own elimination (10). This difference in metabolism may be an advantage for OXC over CBZ with regard to possible drug interactions. This study was undertaken to investigate the effect of repeated doses of ERY on the pharmacokinetics of OXC in healthy volunteers.
Oxcarbazepine & erythromycin: no interaction Material and methods
Analysis of oxcarbazepine and its metabolites
The clinical part of this study was performed at the Department of Pharmacology and Toxicology of the University of Kuopio in Finland. All plasma analyses and validation of the analytical method were performed at the Vaajasalo Hospital in Kortejoki, Finland. Eight healthy adult volunteers aged between 20 and 26 years, ( 5 women, 3 men) participated in this study. Their weights ranged from 53 to 70 kg and their heights from 160 to 185 cm. All had normal results in physical examination including pulse rate, blood pressure and ECG. Normal results were also obtained in the laboratory screening test, including haematocrit, haemoglobin, white blood cell count, differential cell count, electrolytes, urea,+reatinine, liver enzymes, total bilirubin and urine analysis. According to the national requirements, informed consent was obtained from each volunteer participating in this study. The study was approved by the Ethics Committee of the University of Kuopio. Additional medication and alcohol consumption were forbidden one week before the start and until the end of the study.
The plasma concentrations of unchanged OXC, MHD, and DHD, were determined simultaneously in the same plasma sample by means of an HPLC method using 9-hydroxymethyl- 1O-carbamoyl-acridine as internal standard. Samples were prepared with Bond-Elut C,, columns and reconstituted in 100 yl of the mobile phase, acetonitrile/lO mM phosphate buffer pH 3.7/methanol(25:68:7). 10 1.11 of the extracted sample was injected onto an analytical C,, column (4.6 x 300 mm, 5 ym particle size). Elution was done at a flow rate of 1.0 ml/min and peaks were detected at 240 nm. The limit of quantitation (LOQ) of the method was about 0.4 pmol/l for all three compounds determined. The within-day and between-day coefficients of variation for the compounds studied at two therapeutic concentrations were 0.9-7.2% (n = 7) and 3.0-10.0% (n = 33), respectively.
Study design, treatments and administration
The study was of an open-label, randomized crossover design. The volunteers were randomly assigned to receive the treatments in the sequence A,B or B,A. Treatment A consisted of a single 600 mg dose of oxcarbazepine (two 300 mg Trileptal@tablets, Batch No. 10/943/1). In Treatment B, the volunteers were treated with 500 mg b.i.d. doses of erythromycin (500 mg Etromycin@tablets, Batch No. 06-91 OF 2-2) at 8 a.m. and 8 p.m. for 7 days. This was considered adequate to inhibit the hepatic oxygenases of the cytochrome P450 family (1). On Day 7, a single 600 mg dose of OXC was administered together with the 500 mg morning dose of ERY. In both treatments the morning doses were taken at 8 a.m. after overnight fasting of at least 10 h. A standard breakfast was given 2 h and lunch 4 h after intake of the medication (in treatment B only on Day 7). Sample collection
Blood samples for the measurement of OXC and its metabolites MHD and D H D were drawn into heparinized tubes just before, and 1, 2, 3,4, 6, 8, 10, 12, 24, 48, 72 and 96 h after intake of the medication. The plasma was separated, transferred to plain tubes, and stored at - 20°C until analysed.
Pharmacokinetic evaluation
Plasma concentration-time profiles of OXC, MHD, and D H D were determined and Cmax, tmax, and AUC values derived. Cmax is the highest observed plasma concentration and tmax the time point when this concentration was observed. The area under the plasma concentration-time curve from 0 h to the time point 96 h, AUC(,-9, h), was calculated according to the linear trapezoidal rule. After the single dose administration of OXC, AUC values of unchanged OXC and of DHD amount to only 3.5% and 4.5% of the AUC values of the main metabolite, MHD. However, as concentrations of OXC and D H D are close to the limit of quantitation of the analytical method, evaluations of kinetics based on findings with these compounds are not completely reliable. Therefore, testing the influence of co-administration of ERY on the pharmacokinetics of OXC relies on the comparison of the measured values of the pharmacologically active monohydroxy derivative, MHD. Results
Clinical observations
There were no relevant changes in the medical status of the volunteers or the laboratory clinical findings at any time during the study. No side effects were reported by the volunteers. Pharmacokinetic observations
Individual plasma concentration-time profiles of MHD were almost identical in all eight subjects after 121
Keranen et al.
--
Table 1. Pharmacokineticsof MHD, OXC, and DHD in treatments A and B
Oxcarbazepine alone M Oxcarbazepine plus Erythromycin
0
k
:
-
a
' .c 20-
MHD
Time (h) Fig. I. Mean plasma concentration-time profiles of the pharmacologically active metabolite (MHD) measured in 8 healthy subjects after a single oral 600 mg dose of oxcarbazepine, and when the same dose was given together with the morning dose on day 7 of repeated treatment with 500 mg b.i.d. doses of erythromycin. The low plasma concentrations of unchanged oxcarbazepine (OXC) are shown in the same graph.
either OXC alone or OXC and ERY but interindividual variability was observed. The mean curves calculated for both treatments are shown in Fig. 1. In five of the eight subjects, differences between the AUC values of M H D calculated for the two treatments were smaller than 10%. The individual AUC values of MHD observed in the two treatments are compared in Fig. 2. The mean values for AUC, Cmax and tmax of MHD are given in Table 1. Values for OXC and
1200
=*
1000
A
.f'
-:a
800 600
L
u)
0
I
0
400
0
3 Q
200 0
B
A Treatment phase
Fig. 2. Individual AUC (0-96 h) values of the pharmacologically active metabolite (MHD) measured in 8 healthy subjects after a single peroral dose of 600 mg of oxcarbazepine (A), and when the same dose was given together with the morning dose on day 7 of repeated treatment with 500 mg b i d . doses of erythromycin (B).
122
Treatment A Compound
alone
Treatment 8 600 mg OXC plus 500 mg erythromycin
AUC (0-96h) [(vnol/l).h] MeanfSD N=8
MHD
765.2f152.5 27.1f8.3 34.3f20.0
781.1f 149.7 26.8f9.8 16.8k19.9
Cmax [pmolll] MeanfSD N=8
MHD
29.9f5.4 6.6f1.8 0.9f0.4
27.6f5.3 7.3f2.5 0.5f0.3
tmax [hl median N=8
MHD
4 1.5 24
4 1 18
600 mg OXC Parameter
oxc
DHD
oxc
DHD
oxc
DHD
D H D are also included, but should be treated with caution. By analysis of variance, the subject, sequence (treatment A,B or B,A) treatment and the period effects was analysed. No significant difference could be detected between the AUC (p = 0.67) and Cmax (p = 0.14) values of M HD observed in the two treatments. Discussion
The co-administration of ERY had no influence on the AUC, Cmax, and tmax of OXC and the pharmacologically active metabolite, MHD. However, ERY had a pronounced effect on the plasma levels of the pharmacologically inactive DHD. The approximate mean values for AUC and Cmax decreased by about 50 % ,although the measurement of such low concentrations is not completely reliable. Though the oxidation of MHD to D H D is reduced, the concentrations of MHD are not significantly increased, since only about 4.5% of MHD is metabolized to DHD. In many instances drug interactions based on cytochrome P450 inhibition may have little clinical significance. However, in the case of drugs with a relatively narrow therapeutic index such as antiepileptics, inhibition may severely compromise efficacy and/or cause unwanted side effects. Therefore, it is important to investigate possible drug inter-actions between inhibitors like ERY and new anti-epileptics. ERY is metabolized in humans to a reactive intermediate that forms stable complexes with some cytochrome P450 isoenzymes (1 1). Drug interactions ensue if these isoenzymes are also responsible for the metabolism of concomitantly administered drugs. ERY is known to increase the plasma levels of other anti-epileptic drugs like carbamazepine, leading to serious side effects (1, 2). Adjustment of
Oxcarbazepine & erythromycin: no interaction the CBZ dose and careful plasma level monitoring are necessary in order to maintain adequate antiepileptic therapy when co-administration of ERY is required. Our study has shown that there is no interaction between ERY and OXC in healthy volunteers. The most likely explanation for this is that the stable complexes formed between cytochrome P450 and the ERY intermediate do not affect the metabolism of OXC to MHD, or the clearance of M D H from the body. However, the effects on D H D plasma levels may show that cytochrome P450 isoenzymes play some role in the minor oxidative pathway which converts M H D to DHD. The clinical implication of this interaction is of no importance, since only 4.5 % of MH D is metabolised to DHD. We conclude that antiepileptic therapy with oxcarbazepine offers a clinical advantage over carbamazepine especially when co-administration of erythromycin is required. Acknowledgement The authors are grateful to J.-M. Cardot for his contributions to the statistical analysis.
References
2. BARZAGHI N, GATTI G, CREMAF, MONTELEONE M, AMIONEC, LEONEL, PERUCCA E. Inhibition by erythromycin of the conversion of carbamazepine to its 10,ll-epoxide metabolite. Br J Clin Pharmac 1987: 24: 836-838. 3. EICHELBAUM M, TOMSON T, TYBRING G, BERTILSSON L. Carbamazepine metabolism in man. Induction and pharmacogenetic aspects. Clin Pharmacokinet 1985: 10: 80-90. 4. FAICLE JW, FELDMANN KF. Carbamazepine: biotransforDM, PENRYJK, PIPPENGER CE, mation. In: WOODBURY eds. Antiepileptic drugs. New York: Raven Press, 1982:483495. 5. PISANIF, PERUCCA E, DI PERRIR. Clinically relevant antiepileptic drug interactions. J Int Med Res 1990: 18: 1-15. 6. Editorial. Oxcarbazepine. Lancet 1989, 11: 196-198. 7. FAIGLEJW, MENGEGP. Pharmacokinetic and metabolic features of oxcarbazepine and their clinical significance:comparison with carbamazepine. Int Clin Pharmacol 1990: 5: SUPPI. 1, 73-82. 8. FAIGLE JW, MENGEGP. Metabolic characteristics of oxcarbazepine (Trileptal@)and their beneficial implications for enzyme induction and drug interaction. Behav Neurol 1990: 3: SUPPI.1: 21-30. KF, FAIGLE JW, KRIEMLER HP, 9. SCHUTZH, FELDMANN WINKLERT. The metabolism of ''C-oxcarbazepine in man. Xenobiotica 1986: 16: 769-778. G, BEASTALL GH et al. 10. LARKINJG, MCKEEPJ, FORREST Evidence of lack of auto- and hetero-induction with the novel anticonvulsant oxcarbazepine in healthy volunteers. Br J Clin Pharmac 1991: 31: 65-71. T. New and old macrolides, interactions and cy11. MIDVEDT tochrome P450. In: DUKESMNG, BEELEYL, eds. Side effects of drugs animal 14, Amsterdam: Elsevier, 1990: 220228.
1. GOULDEN KJ, CAMFIELD P, DOOLEYJM et al. Clinical and laboratory observations. Severe carbamazepine intoxication after co-administration of erythromycin. J Pediatrics 1986: 109: 135-138.
123
J
J
Keranen T, Jolkkonen J, Jensen PK, Menge GP, Andersson P. Absence of interaction between oxcarbazepine and erythromycin. Acta Neurol Scand 1992: 86: 120-123.
T. Keranen', J. Jolkkonen2 P. K. Jensen4, G. P. Menge', P. Andersson
'
When erythromycin (ERY) is co-administrated with the antiepileptic carbamazepine (CBZ), a drug interaction may cause an increase in CBZ plasma concentrations, which can result in CBZ related toxic symptoms. This cross-over study was designated to investigate whether ERY influences the pharmacokinetics of the new antiepileptic oxcarbazepine (OXC) and its metabolites. In 8 healthy volunteers there were no significant differences in AUC, peak plasma concentrations or time to peak concentration when OXC was administered either with or without ERY. The results of this study suggest that OXC may offer an important advantage over CBZ especially when concomitant therapy with ERY is required.
It is well documented in the literature that erythromycin (ERY) causes plasma concentrations of carbamazepine (CBZ) to increase, resulting in CBZ related toxic symptoms such as disturbances of vision, ataxia and dizziness (1). The co-administration of ERY prolongs the elimination half-life of CBZ and reduces its clearance. Serum levels of the metabolite, CBZ-epoxide, are markedly decreased during co-administration of ERY, indicating that the oxidative metabolic pathway is inhibited (2). CBZ is metabolized mainly by oxidative reactions. Repeated administration of CBZ leads to induction of hepatic oxygenases of the cytochrome P450 family. Owing to this auto-induction effect, the total plasma clearance increases in patients during carbamazepine therapy (3,4). Enzyme inducing drugs like phenobarbital or phenytoin can further increase the plasma clearance of CBZ when administered concomitantly. In contrast, enzyme inhibiting drugs like propoxyphene, verapamil or viloxazine counteract the inductive properties of both CBZ and other enzyme inducing drugs (5). Oxcarbazepine (OXC), 10,ll-dihydro - 100x0-5H-dibenz- [b,f] -azepine-5-carboxamide, TriSummary results have been presented at the Annual Meeting of the American Epilepsy Society, San Diego, California, Nov. 11-14, 1990 in Poster Session IV: Antiepileptic Drugs, and were published as in abstract in AES Proceedings in Epilepsia, 31(5): 1990: 641.
120
Department of Pharmacology and Toxicology, University of Kuopio, * Vaajasalo Hospital, Kortejoki, Kuopio, CIBA-GEIGY OY, Helsinki, Finland, Research and Development, Pharmaceuticals Division, CIBA-GEIGY Limited, Basle, Switzerland
Key words: epilepsy; anticonvulsants; erythromycin; drug interactions G.P. Menge, Pharma Research and Development, K-136.2.93. CIBA-GEIGY Limited, CH-4002 Basle, Switzerland Accepted for publication November 29, 1991
leptal@, is a newly introduced anti-epileptic drug which has been shown to be as effective as CBZ in patients suffering from partial seizu'res, with or without secondary generalization, and generalized tonicclonic seizures (6). Although CBZ and OXC are chemically related, their metabolic pathways in man are completely different. In contrast to CBZ, the biotransformation of OXC is controlled mainly by non-inducible hepatic cytosolic reductases (7, 8). In humans OXC is rapidly and almost completely reduced to the antiepileptically active monohydroxy derivative (MHD), 10,ll-dihydro- lO-hydroxy-5H-dibenz-[b,f]azepine-5-carboxamide, which is thought to be mainly responsible for the anti-epileptic effect of OXC. After single oral dose administration, 80 % of an OXC dose is eliminated as MHD and its glucuronide conjugate in the urine. A small amount of MHD is further transformed to the pharmacologically inactive dihydroxy derivative (DHD), 10,lldihydro- lo-, 1l-dihydroxy-5H-dibenz-[b,f]-azepineScarboxamide (9). Unlike CBZ, OXC does not induce enzymes that increase the rate of its own elimination (10). This difference in metabolism may be an advantage for OXC over CBZ with regard to possible drug interactions. This study was undertaken to investigate the effect of repeated doses of ERY on the pharmacokinetics of OXC in healthy volunteers.
Oxcarbazepine & erythromycin: no interaction Material and methods
Analysis of oxcarbazepine and its metabolites
The clinical part of this study was performed at the Department of Pharmacology and Toxicology of the University of Kuopio in Finland. All plasma analyses and validation of the analytical method were performed at the Vaajasalo Hospital in Kortejoki, Finland. Eight healthy adult volunteers aged between 20 and 26 years, ( 5 women, 3 men) participated in this study. Their weights ranged from 53 to 70 kg and their heights from 160 to 185 cm. All had normal results in physical examination including pulse rate, blood pressure and ECG. Normal results were also obtained in the laboratory screening test, including haematocrit, haemoglobin, white blood cell count, differential cell count, electrolytes, urea,+reatinine, liver enzymes, total bilirubin and urine analysis. According to the national requirements, informed consent was obtained from each volunteer participating in this study. The study was approved by the Ethics Committee of the University of Kuopio. Additional medication and alcohol consumption were forbidden one week before the start and until the end of the study.
The plasma concentrations of unchanged OXC, MHD, and DHD, were determined simultaneously in the same plasma sample by means of an HPLC method using 9-hydroxymethyl- 1O-carbamoyl-acridine as internal standard. Samples were prepared with Bond-Elut C,, columns and reconstituted in 100 yl of the mobile phase, acetonitrile/lO mM phosphate buffer pH 3.7/methanol(25:68:7). 10 1.11 of the extracted sample was injected onto an analytical C,, column (4.6 x 300 mm, 5 ym particle size). Elution was done at a flow rate of 1.0 ml/min and peaks were detected at 240 nm. The limit of quantitation (LOQ) of the method was about 0.4 pmol/l for all three compounds determined. The within-day and between-day coefficients of variation for the compounds studied at two therapeutic concentrations were 0.9-7.2% (n = 7) and 3.0-10.0% (n = 33), respectively.
Study design, treatments and administration
The study was of an open-label, randomized crossover design. The volunteers were randomly assigned to receive the treatments in the sequence A,B or B,A. Treatment A consisted of a single 600 mg dose of oxcarbazepine (two 300 mg Trileptal@tablets, Batch No. 10/943/1). In Treatment B, the volunteers were treated with 500 mg b.i.d. doses of erythromycin (500 mg Etromycin@tablets, Batch No. 06-91 OF 2-2) at 8 a.m. and 8 p.m. for 7 days. This was considered adequate to inhibit the hepatic oxygenases of the cytochrome P450 family (1). On Day 7, a single 600 mg dose of OXC was administered together with the 500 mg morning dose of ERY. In both treatments the morning doses were taken at 8 a.m. after overnight fasting of at least 10 h. A standard breakfast was given 2 h and lunch 4 h after intake of the medication (in treatment B only on Day 7). Sample collection
Blood samples for the measurement of OXC and its metabolites MHD and D H D were drawn into heparinized tubes just before, and 1, 2, 3,4, 6, 8, 10, 12, 24, 48, 72 and 96 h after intake of the medication. The plasma was separated, transferred to plain tubes, and stored at - 20°C until analysed.
Pharmacokinetic evaluation
Plasma concentration-time profiles of OXC, MHD, and D H D were determined and Cmax, tmax, and AUC values derived. Cmax is the highest observed plasma concentration and tmax the time point when this concentration was observed. The area under the plasma concentration-time curve from 0 h to the time point 96 h, AUC(,-9, h), was calculated according to the linear trapezoidal rule. After the single dose administration of OXC, AUC values of unchanged OXC and of DHD amount to only 3.5% and 4.5% of the AUC values of the main metabolite, MHD. However, as concentrations of OXC and D H D are close to the limit of quantitation of the analytical method, evaluations of kinetics based on findings with these compounds are not completely reliable. Therefore, testing the influence of co-administration of ERY on the pharmacokinetics of OXC relies on the comparison of the measured values of the pharmacologically active monohydroxy derivative, MHD. Results
Clinical observations
There were no relevant changes in the medical status of the volunteers or the laboratory clinical findings at any time during the study. No side effects were reported by the volunteers. Pharmacokinetic observations
Individual plasma concentration-time profiles of MHD were almost identical in all eight subjects after 121
Keranen et al.
--
Table 1. Pharmacokineticsof MHD, OXC, and DHD in treatments A and B
Oxcarbazepine alone M Oxcarbazepine plus Erythromycin
0
k
:
-
a
' .c 20-
MHD
Time (h) Fig. I. Mean plasma concentration-time profiles of the pharmacologically active metabolite (MHD) measured in 8 healthy subjects after a single oral 600 mg dose of oxcarbazepine, and when the same dose was given together with the morning dose on day 7 of repeated treatment with 500 mg b.i.d. doses of erythromycin. The low plasma concentrations of unchanged oxcarbazepine (OXC) are shown in the same graph.
either OXC alone or OXC and ERY but interindividual variability was observed. The mean curves calculated for both treatments are shown in Fig. 1. In five of the eight subjects, differences between the AUC values of M H D calculated for the two treatments were smaller than 10%. The individual AUC values of MHD observed in the two treatments are compared in Fig. 2. The mean values for AUC, Cmax and tmax of MHD are given in Table 1. Values for OXC and
1200
=*
1000
A
.f'
-:a
800 600
L
u)
0
I
0
400
0
3 Q
200 0
B
A Treatment phase
Fig. 2. Individual AUC (0-96 h) values of the pharmacologically active metabolite (MHD) measured in 8 healthy subjects after a single peroral dose of 600 mg of oxcarbazepine (A), and when the same dose was given together with the morning dose on day 7 of repeated treatment with 500 mg b i d . doses of erythromycin (B).
122
Treatment A Compound
alone
Treatment 8 600 mg OXC plus 500 mg erythromycin
AUC (0-96h) [(vnol/l).h] MeanfSD N=8
MHD
765.2f152.5 27.1f8.3 34.3f20.0
781.1f 149.7 26.8f9.8 16.8k19.9
Cmax [pmolll] MeanfSD N=8
MHD
29.9f5.4 6.6f1.8 0.9f0.4
27.6f5.3 7.3f2.5 0.5f0.3
tmax [hl median N=8
MHD
4 1.5 24
4 1 18
600 mg OXC Parameter
oxc
DHD
oxc
DHD
oxc
DHD
D H D are also included, but should be treated with caution. By analysis of variance, the subject, sequence (treatment A,B or B,A) treatment and the period effects was analysed. No significant difference could be detected between the AUC (p = 0.67) and Cmax (p = 0.14) values of M HD observed in the two treatments. Discussion
The co-administration of ERY had no influence on the AUC, Cmax, and tmax of OXC and the pharmacologically active metabolite, MHD. However, ERY had a pronounced effect on the plasma levels of the pharmacologically inactive DHD. The approximate mean values for AUC and Cmax decreased by about 50 % ,although the measurement of such low concentrations is not completely reliable. Though the oxidation of MHD to D H D is reduced, the concentrations of MHD are not significantly increased, since only about 4.5% of MHD is metabolized to DHD. In many instances drug interactions based on cytochrome P450 inhibition may have little clinical significance. However, in the case of drugs with a relatively narrow therapeutic index such as antiepileptics, inhibition may severely compromise efficacy and/or cause unwanted side effects. Therefore, it is important to investigate possible drug inter-actions between inhibitors like ERY and new anti-epileptics. ERY is metabolized in humans to a reactive intermediate that forms stable complexes with some cytochrome P450 isoenzymes (1 1). Drug interactions ensue if these isoenzymes are also responsible for the metabolism of concomitantly administered drugs. ERY is known to increase the plasma levels of other anti-epileptic drugs like carbamazepine, leading to serious side effects (1, 2). Adjustment of
Oxcarbazepine & erythromycin: no interaction the CBZ dose and careful plasma level monitoring are necessary in order to maintain adequate antiepileptic therapy when co-administration of ERY is required. Our study has shown that there is no interaction between ERY and OXC in healthy volunteers. The most likely explanation for this is that the stable complexes formed between cytochrome P450 and the ERY intermediate do not affect the metabolism of OXC to MHD, or the clearance of M D H from the body. However, the effects on D H D plasma levels may show that cytochrome P450 isoenzymes play some role in the minor oxidative pathway which converts M H D to DHD. The clinical implication of this interaction is of no importance, since only 4.5 % of MH D is metabolised to DHD. We conclude that antiepileptic therapy with oxcarbazepine offers a clinical advantage over carbamazepine especially when co-administration of erythromycin is required. Acknowledgement The authors are grateful to J.-M. Cardot for his contributions to the statistical analysis.
References
2. BARZAGHI N, GATTI G, CREMAF, MONTELEONE M, AMIONEC, LEONEL, PERUCCA E. Inhibition by erythromycin of the conversion of carbamazepine to its 10,ll-epoxide metabolite. Br J Clin Pharmac 1987: 24: 836-838. 3. EICHELBAUM M, TOMSON T, TYBRING G, BERTILSSON L. Carbamazepine metabolism in man. Induction and pharmacogenetic aspects. Clin Pharmacokinet 1985: 10: 80-90. 4. FAICLE JW, FELDMANN KF. Carbamazepine: biotransforDM, PENRYJK, PIPPENGER CE, mation. In: WOODBURY eds. Antiepileptic drugs. New York: Raven Press, 1982:483495. 5. PISANIF, PERUCCA E, DI PERRIR. Clinically relevant antiepileptic drug interactions. J Int Med Res 1990: 18: 1-15. 6. Editorial. Oxcarbazepine. Lancet 1989, 11: 196-198. 7. FAIGLEJW, MENGEGP. Pharmacokinetic and metabolic features of oxcarbazepine and their clinical significance:comparison with carbamazepine. Int Clin Pharmacol 1990: 5: SUPPI. 1, 73-82. 8. FAIGLE JW, MENGEGP. Metabolic characteristics of oxcarbazepine (Trileptal@)and their beneficial implications for enzyme induction and drug interaction. Behav Neurol 1990: 3: SUPPI.1: 21-30. KF, FAIGLE JW, KRIEMLER HP, 9. SCHUTZH, FELDMANN WINKLERT. The metabolism of ''C-oxcarbazepine in man. Xenobiotica 1986: 16: 769-778. G, BEASTALL GH et al. 10. LARKINJG, MCKEEPJ, FORREST Evidence of lack of auto- and hetero-induction with the novel anticonvulsant oxcarbazepine in healthy volunteers. Br J Clin Pharmac 1991: 31: 65-71. T. New and old macrolides, interactions and cy11. MIDVEDT tochrome P450. In: DUKESMNG, BEELEYL, eds. Side effects of drugs animal 14, Amsterdam: Elsevier, 1990: 220228.
1. GOULDEN KJ, CAMFIELD P, DOOLEYJM et al. Clinical and laboratory observations. Severe carbamazepine intoxication after co-administration of erythromycin. J Pediatrics 1986: 109: 135-138.
123
