Epilepsia. 2&169-173, 1979. Raven Ress, New York
Short Communication Carbamazepine Revisited in a 'Monkey Model Joan S. Lockard, Rene H. Levy, Larry L. DuCharme, William C. Congdon, and Indravadan H. Pate1 Departments of Neurological Surgery and Pharmaceutical Sciences, University of Washington, Seattle, Washington 98/95
Summary: In a previous study on carbamazepine (Lockard et al., 19741, the problem of its low bioavailability in solid form and its short half-life in monkey were addressed. The present research was designed to evaluate carbamazepine under constant-rate intravenous infusion in our alumina-gel monkey model. Since carbamazepine is insoluble in an aqueous solution, polyethylene glycol 400 was used as the vehicle for administration of this drug to a group of 8 epileptic monkeys. The attenuation of seizures by carbamazepine was not statistically significant since the serum levels of carbamazepine after enzyme induction were less than 2.0 &ml. This study (a) illustrates that some problems in drug evaluation may be insoluble with our present technology even though we are cognizant of them; (b) makes explicit the fact that the efficacy of carbamazepine is a function of adequate serum levels; (c) demonstrates endogenous oscillations of carbamazepine serum concentrations; and (d) reports simultaneous serum levels of carbamazepine and its 10-11 epoxide in the monkey model.
'
A previous study of carbamazepine (Lockard et al., 1974) from our laboratories illustrated the importance of preliminary pharmacokinetics of anticonvulsants prior to efficacy testing. To circumvent the problems of bioavailability and frequent dosing of carbamazepine in primates, a constantrate intravenous infusion, via indwelling catheters, was chosen as the mode of administration. The insolubility of this drug (10 mg/ml in H20, 24°C) in conjunction with its large total body clearance (0.54 liters/ hr/kg) required solubilization in a vehicle of water and 60% PEG (greater concentrations
of PEG were too viscous). The maximum delivery rate (10-15 mg/hr) resulted in steady-state serum levels of 1-2 pg/ml initially and 60% of these levels after auto induction (Fig. 1). These conditions were utilized in a group of 8 rhesus monkeys (Macaca rnulatta) rendered chronically epileptic by cortical injections of aluminum hydroxide. The animals were equipped with two indwelling catheters for drug administration and blood sampling, respectively, as well as with EEG plugs for quantification of paroxysms. In addition to the detection of clinical seizures
Received July 13, 1978. Key words: Carbamazepine-Anticonvulsant-Epilepsy-Monkey. Dr.hckard and Dr.Levy are Research affiliates of the Child Development and Mental Retardation Center, University of Washington, Seattle, Washington.
169
I 70
J . S. LOCKARD ET A L . CARBAYAZEPINE
'T
N=8
FROM COMMENCEMENT OF M U G INFUSION
FIG. 1. Mean serum concentration (pdml) and standard deviations of carbamazepine in 8 monkeys as a function of constant-rate intravenous infusion of 5 and 10 mg/ml/hr, respectively.
accomplishable automatically by a closed circuit TV video tape monitoring system (Lockard et al., 1976), an EEG record was taken for each animal twice a week for 20 min during the day as well as for 12 hr during the night every 3 weeks for both bursting activity and for sleep staging. The animals were on a 12 hr light (starting at 0600 hr) and 12 hr dark cycle (beginning at 1800 hr) . During the drug treatment period, carbamazepine was infused intravenously at a constant rate of 5 mg/ml/hr for the first 2 days and 10 mg/ml/hr on all subsequent days. Concentrations of carbamazepine were obtained (a) during the initial infusion, (b) twice weekly thereafter, (c) during one 24 hr series per monkey of one sample every 3 hr, and (d) during the drug elimination stage. The serum samples were analyzed by gas-liquid chromatography (GLC) mass spectrometry for carbamazepine and its 10-11 epoxide, using the technique of Trager et al. (1978). Since carbamazepine at 5 - 10 mg/ml/hr self-induced its own metabolism, its steady
Epilepsia. Vol. 20, April 1979
state serum levels were well below 2pg/ml, which were not efficacious in terms of seizure frequency (Fig. 2). This finding is consistent with the previous study by Lockard et al. (1974) and, with one exception (Meinardi and Magnus, 1974), the vast majority of clinical studies in man (e.g., Kutt and Louis, 1972; Kutt and Penry, 1974; Eadie, 1974;1976; Schneider, 1975; Richens, 1976; Monaco et al., 1976; Troupin et al., 1977). Although David and Grewal (1976) report therapeutic effects of carbamazepine in alumina-gel monkeys, no blood levels were given. Carbamazepine, under constant-rate infusion, manifested diurnal oscillations in serum concentration, as illustrated in 3 monkeys in Fig. 3. Even though this drug was generally not efficacious at serum levels below 2pglm1, it may have influenced overt seizures during the night when its circadian concentration oscillations peaked, since the correlation between EEG and interictal bursts and seizures was somewhat dissociated at the time. Mean EEG bursts per minute correlated 0.98 0, < 0.02) with
CARBAMAZEPINE REVISITED IN MONKEY MODEL
171
ONE WEEK BARS
FIG. 2. Mean daily seizure frequency (8 monkeys) during base-line periods ( 1 and 2) and during carbamazepine at a constant-rate intravenous solution of 10 mg/ml/hr.
mean daily seizure frequency during no drug base-line periods. However, this relationship diminished to 0.70 during carbamazepine administration and was not statistically reliable (p > 0.05). The overnight EEG records revealed a trend (0.10 < p > 0.05>’of (a) decreasing percent time spent in sleep as the study progressed, irrespective of treatments; (b) an increase over base-line periods in stage 3 sleep during carbamazepine; (c) a concomitant in-
crease in mean EEG bursts per minute during stages 2 and 3 of sleep; and (d) a statistically significant increase (r = 2.74, df = 5 , p 0.05) in percent awake during the postdrug period as compared to the treatment period of carbamazepine. In general, it would seem that carbamazepine administration increased sleep with a corresponding increase in EEG bursts but not overt seizures. A decrease in both EEG paroxysms and seizures was demonstrated for valproic
-=
CARBAMAZEPINE
TIM
n
im
a
0
up
4
rn
10
w
L
Dorh
FIG. 3. Diurnal oscillations (24 hr) of serum concentration (pg/ml) of carbamazepine in 3 monkeys during steady state, constant-rate intravenous infusion of 10 mg/ml/hr.
Epilepsia, Vol. 20, April 1979
J . S. LOCKARD ET AL.
I 72 2-
'1
CARBAMAZEPINE
N N= = 88
E
5
a
W
.5.
0 1
.
0
HOURS
1 1.5 2 DRUG WITHDRAWAL
2.5
4
FIG. 4. Mean serum concentration (pdrnl)and standard deviations of carbamazepine (8 monkeys) at steady state and after discontinuance of constant-rate intravenous infusion of 10 mg/ mVhr.
acid by Lockard et al. (1977) during similar but more extensive diurnal oscillations. The 10- 11 epoxide of carbamazepine was reliably measured by mass spectrometry in the present study, Table 1, and followed a similar time course in its metabolism as the parent drug (Patel et al., in press). The question of its own efficacy remains unanswered. The preliminary pharmacokinetics of carbamazepine (Lockard et al., 1974) identified explicitly the problems involved in the evaluation of this drug in animal models. For example, a constant-rate intravenous administration of the drug circumvented its short half-life as illustrated in Fig. 4. However, as is obvious TABLE 1. Steady state levels of carbamazepine and its 10-1I epoxide during efficacy testing Carbamazepine
(rdm
Epoxide (ndml)
Monkey #
Mean
SD
Mean
SD
1 2 4 5 8 9 11 12
1.14 1.34 1.79 1.25 1.45 0.82 1.05 1.41
0.49 0.48 0.21 0.29 0.19 0.14 0.15 0.33
56.16 52.11 90.74 41.66 101.00 39.46 60.56 55.91
24.71 23.56 32.44 6.45 26.46 8.35 7.56 17.42
Group Mean and SD
1 .'28
Epilepsia, Vol. 20, April 1979
62.20 0.29
22.17
from the outcome of the present study, an awareness of other difficulties in testing this drug, e.g., its insolubility, did not result in an empirical solution. ACKNOWLEDGMENT This project was supported by NIH Research Contract NO1-NS- 1-2282 and Research Grant NS 04053 awarded by the National Institutes of Neurological and Communicative Disorders and Stroke, Public Health Service, Department of Health, Education and Welfare. REFERENCES David, J and Grewal RS. Effect of carbamazepine (TegretoP) on seizure and EEG patterns in monkeys with alumina-induced focal motor and hippocampal foci. Epilepsia 17415-422, 1976. Eadie MJ. Laboratory control of anticonvulsant dosage. Drugs 8:386-397, 1974. Eadie MJ. Plasma level monitoring of anticonvulsants. Clin Pharmacokinet 152-66, 1976. Kutt H and Louis S. Anticonvulsant drugs 11: Clinical pharmacological and therapeutic aspects. Drugs 4:256-282, 1972. Kutt H and Penry JK. Usefulness of blood levels of antiepileptic drugs. Arch Neurol31:283-288, 1974. Lockard JS, Levy RH,DuCharme LL, Congdon WC, and Patel IH. Diurnal variation of valproic acid plasma levels and day-night reversal in monkey. Epilepsia 18: 183-189, 1977. Lockard JS, Levy RH, Patel IH, DuCharme LL, and Congdon WC. Dipropylacetic acid and ethosuximide in monkey model: In: P Kellaway and I Petersen (Eds), Quantitative Analytic Studies in Epilepsy. Raven Press, New York, 1976, pp 147- 164.
CARBAMAZEPINE REVISITED IN MONKEY MODEL Lockard JS, Levy RH, Uhlir V, and Farquhar JA. Pharmacokinetic evaluation of anticonvulsants prior to efficacy testing exemplified by carbamazepine in monkey model. Epilepsia 15:351-359, 1974. Meinardi H and Magnus 0. Drug therapy: Clinical application. Handbook of Clinical Neurology 153664-672, 1974. Monaco F, Riccio A, Benna P, Covacich A, Durelli L, Fantini M, Furlan P, Gilli M, Mutani R, Troni W, Gerna M, Morselli P. Further observations on carbamazepine plasma levels in epileptic patients: Relationships with therapeutic and side effects. Neurology 26936-943, 1976. Patel IH, Levy RH, and Trager WF. Pharmacokinetics of carbamazepine-10, 11-epoxide prior to and after auto-induction in rhesus monkeys. J Pharmacol Exp Ther 206507-613, 1978 Richens A. Drug Treatment of Epilepsy. Henry Klimpton Publishers, London, 1976, p 45. Schneider H. Carbamazepine: An attempt to correlate serum levels with anti-epileptic and side effects. In H Schneider et al. (Eds), Clinical Pharmacology of Antiepileptic Drugs, Springer-Verlag. New York, 1975, pp 151-158. Trager WF, Levy RH, Patel IH, and Neal JM. Simultaneous analysis of carbamazepine and carbamazepine- 10, 11-epoxide by GC/CI/MS stable isotope methodology. Atid Lett B1 l(2): 119- 133, 1978. Troupin AS, Ojemapn LM, Halpern LM, Dodrill C, Wilkus R. Friel P, and Feigl P. Carbamazepine: A double-blind comparison with phenytoin. Neurology 27:511-519, 1977.
173
RESUMEN En un estudio previo sobre la carbamazepina realizado por estos autores (1974) se enfocaron 10s problemas de su biodisponibilidad y vida media si se administraba en forma s6lida a monos. La presente investigaci6n ha sido disefiada para valorar la carbamazepina bajo ritmo constante, en infusibn intravenosa, administrada a un modelo de mono preparado con gel d e albmina. Puesto q u e la carbamazepina es insoluble en agua, se ha utilizado el glicol de polietileno 400 como vehiculo para la administraci6n de esta droga a un grupo de 8 monos epilkpticos. L a atenuacibn d e 10s ataques no f u t estadisticamente significativa puesto que 10s niveles stricos de carbamazepina, desputs de la inducci6n enzimltica, fueron menores de 2.0 pg/ml. Este estudio (a) demuestra que algunos problemas de la evaluacibn de drogas pueden ser insolubles con la tecnologia actual incluso siendo conscientes d e su existencia; (b) expone el hecho de que la eficacia de la carbamazepina es funci6n de niveles stricos adecuados; (c) revela oscilaciones end6genas de las concentraciones stricas de carbamazepina; y (d) informa sobre 10s niveles simultlneos de carbamazepina y su 10- 11 ep6xido en el modelo del mono. (A. Portera Sanchez, Madrid)
ZUSAMMENFASSUNG
Eine frilhere Studie der gleichen Autoren Uber Carbamazepin (1974) beschaftigte sich mit seiner niedrigen BioverfUgbarkeit in fester Form und seiner kurzen RESUME Halbwertzeit beim Affen. In der vorliegenden Studie Dans un precedent travail des auteurs sur la car- wird das Carbamazepin unter konstanter intravenbser bamaztpine (1974), le problkme de la biodisponibilitt Infusion im Affenmodell geprilft (fokale Schadigung de la forme solide et de la courte demi-vie chez le durch Aluminium-Gel). Da Carbamazepin in wassriger singe a t t t abordt. La prtsente etude a t t t rtaliste Losung unloslich ist, wurde PolyBthylen-Glycol 400 pour t v a l u e r I’effet d e la carbamaztpine 51 taux als Vehikel bei einer Gruppe von 8 epileptischen Affen constant par injection intraveineuse chez le singe geprilft. Die Verminderung der Kr”dmpfe durch Carrendu tpileptique par implantation d e gel d‘alumine. bamazepin war statistisch nicht signifikant, da die L a carbamaztpine t t a n t insoluble dans I’eau, le Serumspiegel des Carbamazepin nach Enzymindukpropyltne glycol 400 a ttt utilisk comme solvant pour tion unter 2.0 pg/ml lagen. Carbamazepin induzierte son administration B huit singes tpileptiques. sowohl seinen eigenen Metabolismus als auch den L‘atttnuation des crises par la carbamaztpine n’a pas seines 10- 11 Epoxyds (Messung durch Massenspekt t t statistiquement significative puisque le taux trometrie). Ebenso fanden sich tagliche Schwanstrique de carbamaztpine aprks induction enzyma- kungen des Carbamazepinblutspiegels. Diese Untertique etait inferieur a 2 &ml. Ce travail (a) montre suchung zeigt (a),dab einige Probleme der Beurteilung qu’il subsiste avec notre mtthodologie actuelle, von Medikamenten mit dem gegenwartigen technisquelques problkmes non rtsolus en ce qui concerne chen Rnstzeug unlosbar zu sein scheinen, obwohl wir I’tvaluation d‘un medicament, meme si nous les sie wohl e r k e n n e n ; ( b ) wird deutlich, d a p die connaissons: ( b ) explique q u e I‘efficacitt d e la Wirksamkeit des Carbamazepin an einen aduquaten carbamazepine depend de taux seriques adequat; (c) Serumspiegel gebunden ist; (c) zeigen sich endogene dtmontre les oscillations endogenes de concentrations Schwankungen d e r Carbamazepinserumkonzenseriques de carbamazepine;et (d) rapporte chez le singe tration; (d) wird gleichzeitig fiber Serumspiegel des les taux seriques simultanes de carbamazepine et du Carbamazepin und seines 10- 11 Epoxyds am Affenderive 10-11 epoxyde. modell berichtet. (P. Bouyard, Marseilles)
(D. Scheffner, Heidelberg)
Epilepsia, Vol. 20, April 1979
Short Communication Carbamazepine Revisited in a 'Monkey Model Joan S. Lockard, Rene H. Levy, Larry L. DuCharme, William C. Congdon, and Indravadan H. Pate1 Departments of Neurological Surgery and Pharmaceutical Sciences, University of Washington, Seattle, Washington 98/95
Summary: In a previous study on carbamazepine (Lockard et al., 19741, the problem of its low bioavailability in solid form and its short half-life in monkey were addressed. The present research was designed to evaluate carbamazepine under constant-rate intravenous infusion in our alumina-gel monkey model. Since carbamazepine is insoluble in an aqueous solution, polyethylene glycol 400 was used as the vehicle for administration of this drug to a group of 8 epileptic monkeys. The attenuation of seizures by carbamazepine was not statistically significant since the serum levels of carbamazepine after enzyme induction were less than 2.0 &ml. This study (a) illustrates that some problems in drug evaluation may be insoluble with our present technology even though we are cognizant of them; (b) makes explicit the fact that the efficacy of carbamazepine is a function of adequate serum levels; (c) demonstrates endogenous oscillations of carbamazepine serum concentrations; and (d) reports simultaneous serum levels of carbamazepine and its 10-11 epoxide in the monkey model.
'
A previous study of carbamazepine (Lockard et al., 1974) from our laboratories illustrated the importance of preliminary pharmacokinetics of anticonvulsants prior to efficacy testing. To circumvent the problems of bioavailability and frequent dosing of carbamazepine in primates, a constantrate intravenous infusion, via indwelling catheters, was chosen as the mode of administration. The insolubility of this drug (10 mg/ml in H20, 24°C) in conjunction with its large total body clearance (0.54 liters/ hr/kg) required solubilization in a vehicle of water and 60% PEG (greater concentrations
of PEG were too viscous). The maximum delivery rate (10-15 mg/hr) resulted in steady-state serum levels of 1-2 pg/ml initially and 60% of these levels after auto induction (Fig. 1). These conditions were utilized in a group of 8 rhesus monkeys (Macaca rnulatta) rendered chronically epileptic by cortical injections of aluminum hydroxide. The animals were equipped with two indwelling catheters for drug administration and blood sampling, respectively, as well as with EEG plugs for quantification of paroxysms. In addition to the detection of clinical seizures
Received July 13, 1978. Key words: Carbamazepine-Anticonvulsant-Epilepsy-Monkey. Dr.hckard and Dr.Levy are Research affiliates of the Child Development and Mental Retardation Center, University of Washington, Seattle, Washington.
169
I 70
J . S. LOCKARD ET A L . CARBAYAZEPINE
'T
N=8
FROM COMMENCEMENT OF M U G INFUSION
FIG. 1. Mean serum concentration (pdml) and standard deviations of carbamazepine in 8 monkeys as a function of constant-rate intravenous infusion of 5 and 10 mg/ml/hr, respectively.
accomplishable automatically by a closed circuit TV video tape monitoring system (Lockard et al., 1976), an EEG record was taken for each animal twice a week for 20 min during the day as well as for 12 hr during the night every 3 weeks for both bursting activity and for sleep staging. The animals were on a 12 hr light (starting at 0600 hr) and 12 hr dark cycle (beginning at 1800 hr) . During the drug treatment period, carbamazepine was infused intravenously at a constant rate of 5 mg/ml/hr for the first 2 days and 10 mg/ml/hr on all subsequent days. Concentrations of carbamazepine were obtained (a) during the initial infusion, (b) twice weekly thereafter, (c) during one 24 hr series per monkey of one sample every 3 hr, and (d) during the drug elimination stage. The serum samples were analyzed by gas-liquid chromatography (GLC) mass spectrometry for carbamazepine and its 10-11 epoxide, using the technique of Trager et al. (1978). Since carbamazepine at 5 - 10 mg/ml/hr self-induced its own metabolism, its steady
Epilepsia. Vol. 20, April 1979
state serum levels were well below 2pg/ml, which were not efficacious in terms of seizure frequency (Fig. 2). This finding is consistent with the previous study by Lockard et al. (1974) and, with one exception (Meinardi and Magnus, 1974), the vast majority of clinical studies in man (e.g., Kutt and Louis, 1972; Kutt and Penry, 1974; Eadie, 1974;1976; Schneider, 1975; Richens, 1976; Monaco et al., 1976; Troupin et al., 1977). Although David and Grewal (1976) report therapeutic effects of carbamazepine in alumina-gel monkeys, no blood levels were given. Carbamazepine, under constant-rate infusion, manifested diurnal oscillations in serum concentration, as illustrated in 3 monkeys in Fig. 3. Even though this drug was generally not efficacious at serum levels below 2pglm1, it may have influenced overt seizures during the night when its circadian concentration oscillations peaked, since the correlation between EEG and interictal bursts and seizures was somewhat dissociated at the time. Mean EEG bursts per minute correlated 0.98 0, < 0.02) with
CARBAMAZEPINE REVISITED IN MONKEY MODEL
171
ONE WEEK BARS
FIG. 2. Mean daily seizure frequency (8 monkeys) during base-line periods ( 1 and 2) and during carbamazepine at a constant-rate intravenous solution of 10 mg/ml/hr.
mean daily seizure frequency during no drug base-line periods. However, this relationship diminished to 0.70 during carbamazepine administration and was not statistically reliable (p > 0.05). The overnight EEG records revealed a trend (0.10 < p > 0.05>’of (a) decreasing percent time spent in sleep as the study progressed, irrespective of treatments; (b) an increase over base-line periods in stage 3 sleep during carbamazepine; (c) a concomitant in-
crease in mean EEG bursts per minute during stages 2 and 3 of sleep; and (d) a statistically significant increase (r = 2.74, df = 5 , p 0.05) in percent awake during the postdrug period as compared to the treatment period of carbamazepine. In general, it would seem that carbamazepine administration increased sleep with a corresponding increase in EEG bursts but not overt seizures. A decrease in both EEG paroxysms and seizures was demonstrated for valproic
-=
CARBAMAZEPINE
TIM
n
im
a
0
up
4
rn
10
w
L
Dorh
FIG. 3. Diurnal oscillations (24 hr) of serum concentration (pg/ml) of carbamazepine in 3 monkeys during steady state, constant-rate intravenous infusion of 10 mg/ml/hr.
Epilepsia, Vol. 20, April 1979
J . S. LOCKARD ET AL.
I 72 2-
'1
CARBAMAZEPINE
N N= = 88
E
5
a
W
.5.
0 1
.
0
HOURS
1 1.5 2 DRUG WITHDRAWAL
2.5
4
FIG. 4. Mean serum concentration (pdrnl)and standard deviations of carbamazepine (8 monkeys) at steady state and after discontinuance of constant-rate intravenous infusion of 10 mg/ mVhr.
acid by Lockard et al. (1977) during similar but more extensive diurnal oscillations. The 10- 11 epoxide of carbamazepine was reliably measured by mass spectrometry in the present study, Table 1, and followed a similar time course in its metabolism as the parent drug (Patel et al., in press). The question of its own efficacy remains unanswered. The preliminary pharmacokinetics of carbamazepine (Lockard et al., 1974) identified explicitly the problems involved in the evaluation of this drug in animal models. For example, a constant-rate intravenous administration of the drug circumvented its short half-life as illustrated in Fig. 4. However, as is obvious TABLE 1. Steady state levels of carbamazepine and its 10-1I epoxide during efficacy testing Carbamazepine
(rdm
Epoxide (ndml)
Monkey #
Mean
SD
Mean
SD
1 2 4 5 8 9 11 12
1.14 1.34 1.79 1.25 1.45 0.82 1.05 1.41
0.49 0.48 0.21 0.29 0.19 0.14 0.15 0.33
56.16 52.11 90.74 41.66 101.00 39.46 60.56 55.91
24.71 23.56 32.44 6.45 26.46 8.35 7.56 17.42
Group Mean and SD
1 .'28
Epilepsia, Vol. 20, April 1979
62.20 0.29
22.17
from the outcome of the present study, an awareness of other difficulties in testing this drug, e.g., its insolubility, did not result in an empirical solution. ACKNOWLEDGMENT This project was supported by NIH Research Contract NO1-NS- 1-2282 and Research Grant NS 04053 awarded by the National Institutes of Neurological and Communicative Disorders and Stroke, Public Health Service, Department of Health, Education and Welfare. REFERENCES David, J and Grewal RS. Effect of carbamazepine (TegretoP) on seizure and EEG patterns in monkeys with alumina-induced focal motor and hippocampal foci. Epilepsia 17415-422, 1976. Eadie MJ. Laboratory control of anticonvulsant dosage. Drugs 8:386-397, 1974. Eadie MJ. Plasma level monitoring of anticonvulsants. Clin Pharmacokinet 152-66, 1976. Kutt H and Louis S. Anticonvulsant drugs 11: Clinical pharmacological and therapeutic aspects. Drugs 4:256-282, 1972. Kutt H and Penry JK. Usefulness of blood levels of antiepileptic drugs. Arch Neurol31:283-288, 1974. Lockard JS, Levy RH,DuCharme LL, Congdon WC, and Patel IH. Diurnal variation of valproic acid plasma levels and day-night reversal in monkey. Epilepsia 18: 183-189, 1977. Lockard JS, Levy RH, Patel IH, DuCharme LL, and Congdon WC. Dipropylacetic acid and ethosuximide in monkey model: In: P Kellaway and I Petersen (Eds), Quantitative Analytic Studies in Epilepsy. Raven Press, New York, 1976, pp 147- 164.
CARBAMAZEPINE REVISITED IN MONKEY MODEL Lockard JS, Levy RH, Uhlir V, and Farquhar JA. Pharmacokinetic evaluation of anticonvulsants prior to efficacy testing exemplified by carbamazepine in monkey model. Epilepsia 15:351-359, 1974. Meinardi H and Magnus 0. Drug therapy: Clinical application. Handbook of Clinical Neurology 153664-672, 1974. Monaco F, Riccio A, Benna P, Covacich A, Durelli L, Fantini M, Furlan P, Gilli M, Mutani R, Troni W, Gerna M, Morselli P. Further observations on carbamazepine plasma levels in epileptic patients: Relationships with therapeutic and side effects. Neurology 26936-943, 1976. Patel IH, Levy RH, and Trager WF. Pharmacokinetics of carbamazepine-10, 11-epoxide prior to and after auto-induction in rhesus monkeys. J Pharmacol Exp Ther 206507-613, 1978 Richens A. Drug Treatment of Epilepsy. Henry Klimpton Publishers, London, 1976, p 45. Schneider H. Carbamazepine: An attempt to correlate serum levels with anti-epileptic and side effects. In H Schneider et al. (Eds), Clinical Pharmacology of Antiepileptic Drugs, Springer-Verlag. New York, 1975, pp 151-158. Trager WF, Levy RH, Patel IH, and Neal JM. Simultaneous analysis of carbamazepine and carbamazepine- 10, 11-epoxide by GC/CI/MS stable isotope methodology. Atid Lett B1 l(2): 119- 133, 1978. Troupin AS, Ojemapn LM, Halpern LM, Dodrill C, Wilkus R. Friel P, and Feigl P. Carbamazepine: A double-blind comparison with phenytoin. Neurology 27:511-519, 1977.
173
RESUMEN En un estudio previo sobre la carbamazepina realizado por estos autores (1974) se enfocaron 10s problemas de su biodisponibilidad y vida media si se administraba en forma s6lida a monos. La presente investigaci6n ha sido disefiada para valorar la carbamazepina bajo ritmo constante, en infusibn intravenosa, administrada a un modelo de mono preparado con gel d e albmina. Puesto q u e la carbamazepina es insoluble en agua, se ha utilizado el glicol de polietileno 400 como vehiculo para la administraci6n de esta droga a un grupo de 8 monos epilkpticos. L a atenuacibn d e 10s ataques no f u t estadisticamente significativa puesto que 10s niveles stricos de carbamazepina, desputs de la inducci6n enzimltica, fueron menores de 2.0 pg/ml. Este estudio (a) demuestra que algunos problemas de la evaluacibn de drogas pueden ser insolubles con la tecnologia actual incluso siendo conscientes d e su existencia; (b) expone el hecho de que la eficacia de la carbamazepina es funci6n de niveles stricos adecuados; (c) revela oscilaciones end6genas de las concentraciones stricas de carbamazepina; y (d) informa sobre 10s niveles simultlneos de carbamazepina y su 10- 11 ep6xido en el modelo del mono. (A. Portera Sanchez, Madrid)
ZUSAMMENFASSUNG
Eine frilhere Studie der gleichen Autoren Uber Carbamazepin (1974) beschaftigte sich mit seiner niedrigen BioverfUgbarkeit in fester Form und seiner kurzen RESUME Halbwertzeit beim Affen. In der vorliegenden Studie Dans un precedent travail des auteurs sur la car- wird das Carbamazepin unter konstanter intravenbser bamaztpine (1974), le problkme de la biodisponibilitt Infusion im Affenmodell geprilft (fokale Schadigung de la forme solide et de la courte demi-vie chez le durch Aluminium-Gel). Da Carbamazepin in wassriger singe a t t t abordt. La prtsente etude a t t t rtaliste Losung unloslich ist, wurde PolyBthylen-Glycol 400 pour t v a l u e r I’effet d e la carbamaztpine 51 taux als Vehikel bei einer Gruppe von 8 epileptischen Affen constant par injection intraveineuse chez le singe geprilft. Die Verminderung der Kr”dmpfe durch Carrendu tpileptique par implantation d e gel d‘alumine. bamazepin war statistisch nicht signifikant, da die L a carbamaztpine t t a n t insoluble dans I’eau, le Serumspiegel des Carbamazepin nach Enzymindukpropyltne glycol 400 a ttt utilisk comme solvant pour tion unter 2.0 pg/ml lagen. Carbamazepin induzierte son administration B huit singes tpileptiques. sowohl seinen eigenen Metabolismus als auch den L‘atttnuation des crises par la carbamaztpine n’a pas seines 10- 11 Epoxyds (Messung durch Massenspekt t t statistiquement significative puisque le taux trometrie). Ebenso fanden sich tagliche Schwanstrique de carbamaztpine aprks induction enzyma- kungen des Carbamazepinblutspiegels. Diese Untertique etait inferieur a 2 &ml. Ce travail (a) montre suchung zeigt (a),dab einige Probleme der Beurteilung qu’il subsiste avec notre mtthodologie actuelle, von Medikamenten mit dem gegenwartigen technisquelques problkmes non rtsolus en ce qui concerne chen Rnstzeug unlosbar zu sein scheinen, obwohl wir I’tvaluation d‘un medicament, meme si nous les sie wohl e r k e n n e n ; ( b ) wird deutlich, d a p die connaissons: ( b ) explique q u e I‘efficacitt d e la Wirksamkeit des Carbamazepin an einen aduquaten carbamazepine depend de taux seriques adequat; (c) Serumspiegel gebunden ist; (c) zeigen sich endogene dtmontre les oscillations endogenes de concentrations Schwankungen d e r Carbamazepinserumkonzenseriques de carbamazepine;et (d) rapporte chez le singe tration; (d) wird gleichzeitig fiber Serumspiegel des les taux seriques simultanes de carbamazepine et du Carbamazepin und seines 10- 11 Epoxyds am Affenderive 10-11 epoxyde. modell berichtet. (P. Bouyard, Marseilles)
(D. Scheffner, Heidelberg)
Epilepsia, Vol. 20, April 1979
