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Carbamazepine and its epoxide Relation of plasma levels to toxicity and seizure control.

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Carbamazepine and lts
Eooxide: Relation of
PIasrna Levels to Toxicity
and Seizure Contro1
Wiliiam H. Theodore, MD,” P. K. Narang, PhD,?
Mark D. Holmes, MD,’ Pat Reeves,” and Frank J. Nice*
We studied the relation of plasma levels of carbamazepine (CBZ) and carbamazepine 10,11 epoxide
(CBZE), and their ratio to drug toxicity and seizure
control in 7 patients with complex partial seizures. CBZE/CBZ increased with increasing CBZ levels and was
higher when patients were taking phenytoin or valproic
acid. There were weak correlations between CBZ, C B Z
E levels, toxicity scores, and seizure control when patients were taking CBZ alone, but not when other drugs
were given as well. There were no significant differences in the correlation with toxicity score or seizure
frequency between CBZ, CBZ-E, or their sum. Measurement of CBZ-E levels did not provide additional information useful for monitoring clinical response to CBZ
therapy.
Theodore WH, Narang PK, Holmes MD, Reeves P,
Nice FJ. Carbamazepine and its epoxide: relation
of plasma levels to toxicity and seizure control.
Ann Neurol 1989;25:194-196
Carbamazepine (CBZ) is an effective drug in the management of complex partial and secondary generalized
tonic-clonic seizures {i]. Effective dosage, however,
may vary greatly from patient to patient, and the relation of plasma leve1 to seizure control and drug toxicity
is inexact {i]. CBZ’s major metabolite, carbamazepine
10,ll-epoxide (CBZ-E), is an effective anticonvulsant
in animai models {2, 31. Previous reports have suggested that CBZ-E may play a role in the drug’s effect
[4-71. Nevertheless, few systematic studies of the relation between plasma levels of CBZ, CBZ-E, and clinical parameters have been performed. We investigated
the role of CBZ and CBZ-E measurements in following the course of patients treated with CBZ.
Methods
Seven patients with uncontrolled complex partial seizures
were studied on the NIH Clinical Epilepsy section moniFrom the *Chicai Epilepsy Section, Medicai Neurology Branch,
Nationai Institute for Neurologicai and Communicative Disorders
and Stroke, and the tPharmaceuticai Development Service, Clinical
Center, Nationai Institutes of Health, Bethesda, MD.
Received Jun 1, 1988. Accepted for pubiication Jd 12, 1988.
Address correspondence to Dr Theodore, NIH 10/5N-248, Bethesda, MD 20892.
194
toring unit. Four 14-day observation periods included “low-”
and “high-” dose CBZ “monotherapy,” CBZ + phenytoin
(PHT), and CBZ + valproic acid (VPA) (Table I). PHT
levels ranged from 17.1 to 24.6 pg/rnl, and VPA from 75 to
112 &mi. Patients were observed unti1 steady-state drug
levels were reached before beginning a new observation period. CBZ and other drugs were given at constant dosing
intervals throughout the day. Daily drug levels were measured by high-pressure liquid chromatography with uitraviolet detection. A 24-hour urine collection was obtained
during each observation period. Seizure frequency was documented by video-electroencephalographic (EEG) telemetry
and the nursing staff. Toxicity was scored daily on a 1 to 8
scale including limb ataxia, Romberg’s sign, nystagmus, and
diplopia.
Data analysis was performed on an IBM PCXT computer
using the statisticai program “RS-1” (BBM software, Cambridge, MA). Statistics caiculated included correlation coefficients, and Student’s t test for the means of groups with
unpaired data.
Resdts
The ratio of CBZ-E to CBZ plasma levels (CBZ-E/
CBZ) ranged from O. 11 to 0.22 during low-dose CBZ
therapy and from 0.19 to 0.36 during the period of
high-dose CBZ alone (see Table 1). Both PHT and
VPA increased CBZ-E/CBZ. This appeared to be related more closely to a fall in CBZ than to a rise in
CBZ-E levels (see Table 1).Twenty-four hour urinary
excretion of CBZ remained constant or dropped
shghtly when other drugs were added, whereas CBZ-E
excretion increased markedly, suggesting an increased
conversion of CBZ to CBZ-E. The urinary mean
CBZ/CBZ-E was 0.4 k .O3 when the paient was taking CBZ alone, and 0.12 ? .O6 when the patient was
on other drugs; less parent drug was excreted unchanged.
When patients were on CBZ alone (r = 0.82; 140
observations; z = 9.7:p < O.OOOl), or CBZ + PHT (r
= 0.57; z = 5:p < O.OOOi), CBZ and CBZ-E levels
were closely correlated. However, when patients were
on CBZ + VPA, the correlation was not significant (r
= 0.13). On CBZ alone, increasing CBZ levels were
correlated with increasing CBZ-E/CBZ (r = 0.39;p <
0.001). CBZ-E/CBZ was higher during the high-dose
than the low-dose CBZ period (Table 2). However,
when patients were on PHT or VPA, CBZ levels
tended to decline as CBZ-E/CBZ increased, as wouid
be expected from the increased convetsion of CBZ to
CBZ-E (Y = -0.44 for PHT; -0.57 for VPA).
Mean CBZ and CBZ-E levels, and their sum, were
aii higher on days when toxicity scores were incteased
or seizures did not occur (see Table 2). Toxicity scores
were significantly lower, and seizure frequency increased, during the low-dose CBZ period (see Table
2). Correlation coefficients for toxicity scores (on CBZ
alone) were: 0.33 for CBZ, 0.32 for CBZ-E, 0.35 for
Table I. Carbamazepine and Carbamazepine 10,l I Epoxide Plasma Levels" During Four Observation Periods in 7 Patientj
~~
Pauent 1
P e n o i l 2
3
Paaent 2
4
1
2
3
Pauent 3
4
1
2
Patient 4
4
3
i
2
3
Pauent 5
4
i
2
3
Pauent 6
4
1
2
3
4
~
CBZdose 600
(mg/day)
PHT dose
(mg/day)
VPA dose
(mg/day)
CBZ leve1 8
Epoxide 1.1
Ratio
0.13
Panent 7
i
~
2
3
4
~~
1,200 1,200 1,200 600 1,200 1,200 1,200 800 1,600 1,600 1,600 800 1,200 1,200 1,200 600 1,600 1,600 1,600 600 1,400 1,400 1,400 600 1,200 1,200 1,200
300
300
2,500
400
2,500
11.3 6.6 6.9 8.3 13 8
7.8
2.2 2.1 3.5 1.6 2.9 3.5 3
0.190.31 0.51 0.2 0.22 0.43 0.4
400
2,500
8.3 11.4 4.9
0.92 2.2 2.5
0.11 0.190.51
350
1,500
7.7 6
8.4 5.6 6.8
3.2 1.2 1.8 2.3 2.7
0.41 0.190.21 0.42 0.4
300
1,500
6.2 11.8 8.6 10.4 7
10
1.4 4.2 3.5
1.7 1.2 2.5
0.22 0.360.41 0.170.180.25
330
2,250
2,500
9.4 6
8.3 12.2 6.9 84
2.9 2.1 1.5 3.5 3.5
2.1
0.32 0.36 0.18 0.290.52 0.25
"&di.
CBZ
=
carbamazepine; PHT = phenytoin; VPA
= vaiproic acid.
Table 2. Relation Between Carbamazepine, Carbamazepine Epoxide Lmels, Toxicity Scores, and Seizures
(Patients on Carbamazepine Alone)
CBZ Dose
Mean CBZ
Level
LOW
High
p vaiue
6.9
2
1.5"
10.5
?
2.6
Mean Epoxide
Level
1.3
3
Ratio
%
.51
0.19 +- .O6
k
1.2
.28 2.08
<0.0001
Mean Daily
Toxicity Score
Mean Daily
Seizure Frequency
0.96 t 1 . 7
2.5 f 1.4
1 . 8 2 2.2
0.74 ? 1.1
<0.005
<0.001
"Mean f SD pg/mi.
CBZ
= carbamazepine.
their s u m , 0.28 for CBZ-E/CBZ; and for seizure frequency: -0.26, -0.22, -0.27, and -0.17 ( p <
0.05). When patients were taking other drugs, even
these weak relationships were not observed, except in
the case of the CBZ PHT period, when the correlation between CBZ levels and toxicity score was 0.45;
the corresponding value for CBZ-E was O. 18. The predictive value of any of the plasma measurements for
ciinical indices was low.
+
Discussion
Our data do not support the routine use of CBZ-E
measurements in clinical practice. There was a close
correlation of CBZ and CBZ-E levels over a wide
range of plasma levels, especially when patients were
on CBZ alone. We found that PHT and VPA decreased CBZ levels; CBZ-E/CBZ increased in all patients while they were on PHT and in 5 of 7 patients
on VPA. Effects on CBZ-E levels were less consistent,
but urinary CBZ-E excretion increased while CBZ was
constant, suggesting that the main reason for increased
CBZ-E/CBZ was the increased conversion of CBZ to
its epoxide metabolite. There was a weak tendency for
CBZ-EICBZ to increase with increasing CBZ levels.
Similar effects have been observed by other investigators 15, 7-12}. We found a more consistent tendency
of VPA to reduce CBZ levels than have several other
investigators 19, 131. In rats, Chang and Levy found
that CBZ clearance was decreased by VPA, but CBZ-
E formation was increased, due to an even greater inhibition of nonrenal CBZ-E clearance [14]. Tomlin and
colleagues did not find a significant difference of CBZE/CBZ between children on CBZ alone and combination therapy, but 20% of their patients had blood
levels drawn on the first day of drug therapy, which
may have influenced the results [15].
Case reports of patients suffering from CBZ overdoses have not shown that measuring CBZ-E levels
helps to follow resolution of drug toxicity 116-177.
Riva and coworkers found that the correlation of
CBZ-E levels (or CBZ + CBZ-E) with the presence
of nystagmus was no better than that of CBZ alone
[18]. Patients taking a combination of at least three
drugs including CBZ and VPA had increased CBZ-E/
CBZ when side effects were present; in the same
study, the incidence of drowsiness was higher in patients on CBZ + VPA (5/27) than on CBZ alone (2/
27), leading the authors to suggest that increased epoxide levels might play a role in drug toxicity [19}. But
patients with toxicity were taking higher doses of both
VPA and CBZ, making the results harder to interpret
E191.
Children whose seizures reponded to CBZ therapy
had higher CBZ and CBZ-E levels than those whose
seizures persisted; CBZ-E/CBZ was the same in both
groups 1201. Furlanut and associates found that CBZE/CBZ was higher (and CBZ lower) in children with
uncontrolled seizures than with controlled, but it is
Brief Communication: Theodore et ai: Carbamazepine and Its Epoxide
195
uncertain from their report whether the former were
more likely to be on other drugs as well as CBZ 1211.
The conuibution of CBZ-E to the therapeutic effect
of CE2 is uncertain, and the role of CBZ-E plasma
levels has not been established. CBZ levels often are
decreased in patients on combination therapy. The results of our study suggest that, if clinically indicated, it
would be appropriate to increase the CBZ dose to
maintain plasma levels within the therapeutic range,
rather than assuming that the decrease in CBZ due to
PHT or VPA would be compensated by increased
CBZ-E.
References
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epoxide concentrations in epileptics on carbamazepine alone
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8. Dam M, Jensen A, Christiansen J. Plasma levels and effect of
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9. McCauge L, Tyrer JH, Eadie M. Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma.
Therap Drug Monit 1981;3:63-70
10. Rambeck B, May T, Juergens U. S e m concentrations of carbamazepine and its epoxide and dio1 metabolites in epileptic
patients: the influence of dose and comedication. Therap Drug
Monit 1987;9:298-303
I l . Macphee GJ, Butler E, Brodie MJ. Intradose and circadian variation in circuiating carbamazepine and its epoxide in epiieptic
patients: a consequence of autoinduction of metabolism. Epilepsia 1987;28:286-294
12. Elyas AA, Patsalos PN, Brett EM, Lascelles PT. Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine 10, i l epoxide in s e m of
children with epiiepsy. Therap Drug Monit 1986;8:288-292
13. Miesnikowicz FJ, Sherwin AL. Elevation of plasma carbamazepine epoxide levels by comedication with valproate or
primidone. Epilepsia 1985;26:538
14. Chang SL, Levy RH. Inhibitory effect of valproic acid on the
disposition of carbamazepine and carbamazepine 10, 1i epoxide
in the rat. Drug Metab Dispos 1986;14:281-286
5. Tomlin PI, McKinlay I, Smith I. A study on carbamazepine
levels, including estimation of 10-11 epoxy-carbamazepine and
levels in free plasma and saliva. Dev Med Child Neurol
1986;28:713-7 18
6. Suiiivan JB, Rumack BH, Peterson RG. Acute carbamazepine
toxicity resuiting from overdose. Neurology 1981;31:621-624
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carbamazepine-treated epileptic patients: correlation with total
and free plasma concentrations of parent drug and its 10, 11
metabolites. Therap Drug Monit 1985;7:277-282
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The Open Opercdar Sign:
Diagnosis and Signficance
William O. Tatum, DO,' Steven B. Coker, MD,X
Mona Ghobrial, MD,? and Shamel Abd-AllahS
Four children with varying clinical manifestations, but
with the unifying feature of severe developmental delay, had bilateral enlargement of the sylvian fissure
confirmed by magnetic resonance imaging (MRI). Subsequently, we examined 125 consecutive MRI scans of
the heads of pediatric patients, looking for this insuiar
exposure, and did not find it. Pathological correlation in
1child revealed arhinencephaly and abnormal gyral formation; another is known to have migrational abnormalities. We suggest that the open operculum is a sign of
arrested development and is associated with other anomalies and a poor prognosis.
Tatum WO, Coker SB, Ghobriai M, Abd-Allah S. The
open opercular sign: diagnosis and significance.
Ann Neurol 1989;25:196-199
Four children were identified with severe developmentai delay, and an obvious open operculum was
From the *Departments of Neurology and tPathology, Section of
Neuropathology, SSuitch School of Medicine, Loyola University of
Chicago, Chicago, IL.
Received Jun 14, 1988, and in revised form Jui 27. Accepted for
publication Jul 27, 1988.
Address correspondence to Dr Tatum, Loyola University of
Chicago, Department of Neurology, 2160 S. First Ave, Maywood,
IL 60153.
196 Copyright O 1989 by the American Neurologica1 Association
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