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Serum valproate concentrations in epileptic children with favourable responses
Serum Valproate Concentrations in Epileptic Children with Favourable Responses Tatsuya Ishikawa, MD, Chizuko Ogino, MD, Miwako Furuyama, MD, Manabu Kanayama, MD, Atsuko Awaya, MD and Atsuko Yamaguchi, MD
The lower limits of the "therapeutic range" for serum levels of sodium valproate (VPA) were evaluated in epileptic children showing a benign clinical course. Twenty-five outpatients, aged 5 to 16 years, whose seizures were well controlled over three years with VPA alone, were studied. Venous blood was taken 1.1 to 5 hrs after the morning dose. Serum VPA concentrations at steady-state after receiving the maintenance doses to control seizures were determined by enzyme immunoassay. The patients were divided into three groups according to the seizure type and the age at onset; A and B: patients with tonic and/or clonic seizures, aged below 3 yrs (n = 11) and 3 to 11 yrs (n = 6), respectively, C: those with absence seizures, aged 4 to 11 yrs (n = 8). The serum concentrations in A (47.8 ± 21.6 pg/ml, mean ± SD) were significantly (p < 0.02) lower than those in groups Band C (85.2 ± 14.0 and 73.0 ± 17.4 pg/ml, respectively). VPA concentrations below 50 pg/ml were seen in 6 patients (55%) in group A. It was concluded that many epileptic children, whose ages at onset were below 3 yrs, with tonic and/or clonic seizures could be controlled even with low initial serum concentrations below the "therapeutic range". Key words: Valproate, antiepi/eptic drug, therapeutic range, serum concentration, therapeutic drug monitoring, monotherapy, epilepsy, tonic-clonic seizure, absence seizure. Ishikawa T, Ogino C, Furuyama M, Kanayama M, Awaya A, Yamaguchi A. Serum valproate concentrations in epileptic children with favourable responses. Brain Dev 1987; 9: 283-7
Although sodium valproate (VP A) is a widely used antiepileptic drug [1], the "therapeutic range" remains controversial because of the variety of its adverse effects in epileptic patients [2-4]. In recently published textbooks, authors [5-8] describe the "therapeutic range" of 50 to 100 pg/ml in patients, except for the low recommended dose mentioned in Menkes' textbook [9]. But the previous studies cited in the textbooks have been confined to the intractable epileptic patient samples on polypharmacy [10-13]; nevertheless, the "therapeutic range (50-100 pg/ml)" seems to be uniformly used in practice without consideration of the severity of the epileptogenesis. Therefore, we evaluated the lower limit of the "therapeutic range" for VPA, with regard to the age at onset and the seizure type, in epileptic children showing a
From the Department of Pediatrics, Nagoya City University Medical School, Nagoya. Received for pUblication: August 8, 1986. Accepted for publication: November 14, 1986. Correspondence address: Dr. Tatsuya Ishikawa, Department of Pediatrics, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan.
benign clinical course after starting VPA monotherapy.
SUBJECTS AND METHODS The table shows the characteristics of our subjects, who were 25 previously untreated epileptic outpatients attending Nagoya City University Hospital from 1975 to 1982. The patients received VPA (Depakene®, Kyowa Hakko Co Ltd) monotherapy and they were followed at one month intervals, and at each visit the occurrence of seizures was recorded. Their seizures were well controlled over 3.5 years and the present ages (July 1986) ranged from 5 to 16 yrs (mean 11.4). VP A was administered regularly either in solution (patients 1-4, 6-11, 17) or film-coated tablets (patients 5, 12-16, 18-25) in three divided doses. Venous blood was taken at 1.1 to 5.0 hours (Fig 1) after the morning dose following breakfast. Serum VP A concentrations at steadystate after receiving the maintenance doses to control seizures were determined by the homogeneous enzyme immunoassay (EMIT®, Daiichi Kagaku Yakuhin Co Ltd). The patients were divided into three groups according to the age at onset and the seizure type (Table): A and B: patients with tonic and/or clonic seizures, aged below 3 yrs (patients 1-11) and 3 to 11 yrs (patients 12-17),
Table I Characteristics of 25 patients seizure-free over three years Groupa A
Patient/Sex /Age (yrs)
Age at onset (yrs)
Type of epilepsyC
Duration of therapy (yrs)
Follow-up EEGd
* 3
Tonic
SGE
3-
2/F / 10
* 5
Clonic
PGE
4-
3/M/ 5
* 3
Tonic-clonic
PGE
1- 3
E
* 4
Tonic-clonic
PGE
1-
G
* 5
Tonic
PGE
6-12
E
0/ 12
* :3
Tonic
UGE
8-
G
7/ M/ 9
2
* 7
Tonic
PGE
4-
F
8/M/ 8
2
* 5
Tonic
UGE
3- 7
E
9/M/ 5
2
2-
G
3- 6
E
4/F/ 5 6/M/15
8/ 12
10/M/ 7 I1 /F/ 6
C
Seizure type
I/ F/ 7
5/ F/ 12
B
Total seizure frequencyb
7/ 12
Tonic-clonic
PGE or IC
* 5
Tonic
PGE
>10
Tonic-clonic
SGE
:3
7/12-
MR; VSD
G
12/F/ 15
6
6
Clonic
PGE
6-14
E
13/F/ 15
11
* 5
Clonic
UGE
11-15
E
14/F/ 15
11
* 2
Tonic
PE (BECCT)
11-
F
15/M/16
10
3
Atonic
PE
12-
F
16/M/ 15
9
* 3
Clonic
PE
10-
F
17 /F / 8
3
* 3
Tonic
PE
3-
G
18/M/ 14
4
Frequent
Absence
PGE
7-12
E
19/F/15
8
Frequent
Absence
PGE
8-
G
20/F/ 13
8
*Frequent
Absence
PGE
9-
F
21 /F/ 12
8
*Frequent
Absence
PGE
8-
F
22/ M/ I0
4
*Frequent
Absence
PGE
5-
F E
23/F/ 15
8
Frequent
Absence
PGE
9-14
24/F/I O
4
Frequent
Absence
PGE
5-
25 /F/ 15
11
*Frequent
Absence
PGE
12-
Remarks e
MR (IQ 40, WlSC-R) Mental subnormality (lQ 74 , WISC)
MR (lQ 64, TanakaBinet)
F
a: Groups A and B: patients with tonic and/or clonic szs, aged below 3 yrs and 3 to II yrs, respectively, group C: those with absence szs, aged 4 to II yrs. b: Asterisk: no clinical szs after starting the therapy . c: SGE: secondary generalized epilepsy, PGE : primary generalized epilepsy, UGE: undetermined generalized epilepsy, IC: so-called infantile convulsion [14), PE : partial epilepsy, BECCT: benign epilepsy of children with centro-temporal EEG foci. d: E: excellent (no epileptic sz discharges on EEG recording for long periods of time and VPA could be stopped), G: good (no epileptic sz discharges on EEG over two years and VPA could be decreased) , F: fair (no epileptic sz discharges on EEG over two years). e: MR : mental retardation, VSD: ventricular septal defect, IQ : intelligence quotient, WISC : Wechsler intelligence scale for children.
respectively, C: those with absence seizures, aged 4 to 11 yrs (patients 18-25). Seventeen patients (9 in A, 4 in Band 4 in C) experienced no clinical seizures after starting the treatment. Therefore, their initial VP A doses (8.319.0 mg/kg/ day, mean ± SD 13.6 ± 3.4 mg/kg/ day) were maintained. The duration of therapy ranged from 2 to 7 yrs in A, from 4 to 8 yrs in B and from 3 to 6 yrs in C. Electroencephalography (EEG) was performed once per year. Twenty-two patients had no epileptic seizure discharges on the EEG recording over 2 yrs. Eight patients,4 in A (patients 3,5,8, 10),2 in B (patients 12, 13) and 2 in C (patients 18, 23), showed excellent EEG
284 Brain & Development, Vol 9, No 3, 1987
responses for long periods of time and VP A therapy could eventually be stopped (Table).
RESULTS Fig 2 shows the daily doses for the three groups: A, 8.330.5 mg/kg; B, 10.8-22.l mg/kg; and C, 8.3-27 .9 mg/kg. No statistical difference in the daily dose was noted among the three groups. Fig 3 shows the serum concentrations for the three groups: A, 18.0-84.4 pgjrnl; B, 67.7-100.0 pgjml; and C, 51.7-104.4pg/ml. The serum concentrations in group A
o
100
-L
•o
)( 23
·12
100
)( 13
x15
E
C, :t c:
.6
xl? •
.3
c:
ou
x 16
2
'g"
20
o
.9
~
25
X X
5
'"
a. c;; ;:.
E 2 40
'"
.8
20
20
.2
.7
3
4
5
Time of sampling, hrs
Fig 1 The time intervals of the samples as related to the form in which the drug was supplied, and serum valproate concentrations. Triangles indicate patients who took VPA in solution, crosses in film-coated tablets. The numbers with or without underline (VPA was taken before or after breakfast, respectively) correspond the patient number (see Table) .
30
•
B o
• •
o
••
• •• I
47.8 ± 21.6 2
cr
-0-
CIl
.4
CIl
•
•
'"o
."
.,0
40
60
u
21 X
•
c:
X
e'"0.
• •
g
X 14
60
:t c:
o .., x 12
1
~
E
x 19
X 24
x 18
..,
..,~
80
0>
80
o
'"g
]
A
85.2 ± 14.0
73.0± 17.4
B
c
Patient group
Fig 3 The serum valproate concentrations of the three groups according to the age at onset and the seizure type; A and B: patients with tonic and/or clonic seizures, aged below 3 yrs and 3-11 yrs, respectively, C: those with absence seizures, aged 4-11 yrs. Closed circles: patients who could be maintained on initial doses. The concentrations in group A were significantly lower than those in groups Band C (p < 0.02).
0
0 _0_ 0>
.:::.0>
0
0
E
",'
'" "Cl
2
~
'"0
a.
c;; >
~
'iii 0
-0
0
i
•
•
-t-•
•
•
•
•
•
--*-
14.4±6.0
A
• • --
16.6 ± 4.0
18.9 ± 6.7
B
c
Patient group
Fig 2 The daily valproate dose of the three groups according to the age at onset and the seizure type; A and B: patients with tonic and/or clonic seizures, onset < 3 yrs (n = 11) and 3-11 yrs (n = 6), respectively, C: those with absence seizures, onset 4-11 yrs (n =8). Oosed circles indicate patients who experienced no clinical seizures after starting the treatment, open circles indicate those who received more than the initial dose.
Ishikawa et al: VPA concentrations in epilepsy 285
were significantly lower than those in groups Band C (p < 0.02, Student's t test). The level/dose ratio (pg/ml/mg/ kg/day) ranged l.53-6.22 (mean 3.53) in A, 3.19-7.14 (mean 5.37) in Band 2.93-6.23 (mean 4.16) in C. VPA concentrations below the "therapeutic range (50-100 Jlg/ ml)" were found in 6 patients (55%, patients 2,4, 7, 8, 10, 11) in group A, and the concentrations ranged 18.047.0 Jlg/ml . All of 6 patients had had VPA in solution and the interval of time after which the samples had been taken was from 1.4 to 4.25 hours (2.5,1.4,3 .9,4.2,2.0 and 4.3 hrs in patients 2, 4, 7, 8, 10 and 11, respectively). None of 14 patients in group Band C, on the other hand, showed VPA concentrations below the "therapeutic range". There was a significant difference in the number of patients who showed serum VPA concentrations below the "therapeutic range" among group A and groups Band C (p
DISCUSSION Since 1977, fatal hepatic failure [15,16], Reye-like syndrome [17] and hyperammonemia [18] are well known as serious adverse effects of VPA. Recently, the effects of VPA on mitochondrial function have been noted [19, 20]. As for the "therapeutic range" for VPA, many textbooks showed the data derived from the studies published before 1979 [10-13], when few serious adverse effects of VPA were distinct [15] . Therefore, it is necessary to reevaluate the "therapeutic range" for VPA therapy. From the following reasons, we chose the patients with well controlled epilepsy who received VPA monotherapy, and the time of blood sampling from 1.1 to 5 hrs after the morning dose . Most previous studies on the "therapeutic range" have been confined to intractable epileptic patient samples on polypharmacy [10-13]. The study of the therapeutic range of the patients with monopharmacy is, however, more precise than that of the patients with polypharmacy because the interaction between VPA and other antiepileptic drugs significantly affects VPA pharmacokinetics [21-24]. There is a wide spectrum of prognosis in epilepsies, from severe ones such as the Lennox-Gastaut syndrome to benign ones such as primary generalized epilepsy, the former being in the minority [5, 6]. Hence, it is difficult to regard the "therapeutic range" for the severe epileptic groups as representative of all epileptic groups. The time of blood sampling is important, since the half-life of VP A is short [25]. VP A attains maximum concentrations (Cmax) in the serum around 3 (in liquid form) [26] or 2-4 (in mm-coated tablet of Depakene®) hrs after ingestion following meals [27] . Therefore in this study of 10 serum samples in group A, at least, the concentrations would be Cmax. For re-evaluating the lower limit of the "therapeutic range", Cmax is preferable to the minimum
286 Brain & Development, Vol 9, No 3,1987
concentration (Cmin), although several investigators [11, 13] took blood samples before the morning dose (Cmin). In preveous studies [10-13], serum VPA concentrations have been determined by gas chromatography (GC). Homogeneous enzyme immunoassay, which showed good correlation to GC [28] or gave even higher values [29 , 30], was used for the determination of serum VPA concentrations in this study. In our series, most epileptic children, whose ages at onset were below 3 yrs, with tonic and/or clonic seizures (group A) have been controlled with low initial serum concentrations (mean: 47.8 Jlg/ml) below the "therapeutic range". Furthermore, it is likely that 9 patients (82%) in group A could be controlled with even if Cmax was lower, since these children experienced no clinical seizures after starting the therapy. Loiseau recommended a change in the recommended daily dose for VPA in France, and stressed that many patients could be stabilized with low serum concentrations below the so-called therapeutic range [1]. A few authors also described epileptic patients who were controlled with low serum VPA concentrations [31, 32]. In regard to the severity of epileptogenesis, the "therapeutic range (50-100 Jlg/ml)" should be updated, considering possible adverse effects. ACKNOWLEDGMENTS We are grateful for the invaluable contributions of our colleagues, Drs. Kuniju Shimizu, Mikiko Nakazato, Rieko Imanishi, Masumi Noda, Naoko Maki, Michiko Esaki and Hiroe Kawade. We wish to thank Kyowa Hakko Co. Ltd. for the determination of serum VPA concentrations. We are also grateful to Misses Yukari Ito , Akiko Ishihara and Kaori Kato for their expert secretarial assistance in the preparation of the manuscript. The contents of this paper were partly reported at the 28th Annual Meeting of the Japanese Society of Child Neurology , Matsue, 1986. REFERENCES 1. Loiseau P. Rational use of valproate: indications and drug regimen in epilepsy. Epilepsia 1984;25 (Suppll) :S6S-72 . 2. Dreifuss FE. Sodium valproate: a reappraisal. In: Pedley TA , Meldrum BS, eds. Recent advances in epilepsy. Edinburgh: Churchill Livingstone, 1983: 35-46. 3. Schmidt D. Adverse effects of valproate. Epilepsia 1984;25 (Suppll):S44-9. 4. Jeavons PM. Non-dose-related side effects of valproate. Epilepsia 1984;25 (Suppll):SSO-S. 5. Loiseau P, Jallon P. Les epilepsies. Paris: Masson , 1981:243. 6. Farmer TW, Greenwood RS. Paroxysmal disordres. In: Farmer TW, ed. Pediatric neurology. 3rd ed. Philadelphia: Harper & Row, 1983:205-63. 7. Miura H. Therapeutic drug monitoring and practical antiepileptic drug therapy (2). In: Akimoto H, Yamauchi T, eds. Textbook of epileptology (in Japanese) . Tokyo: Iwasaki Gakujutsu, 1984: 301-27 . 8. Miura H. Biochemistry and clinico-pharmacological properties of antiepileptic drugs. In: Arima M, Kamoshita S, Suzuki Y, Seki T, Fukuyama Y, eds. New encyclopedia of pediatrics and related medical sciences 13E. Pediatric neurology V (in Japanese). Tokyo: Nakayama, 1985:221-43.
9. Menkes JH. Textbook of child neurology. 3rd ed. Philadelphia: Lea & Febiger, 1985:639 . 10. Schobben F, van der Kleijn E, Gabreels FJM. Pharmacokinetics of Di-N-propylacetate in epileptic patients. Eur J Clin Pharmacol 1975;8:97-105. 11. Vajda FJE, Drummer OH, Morris PM, McNeil 11, Bladin PF. Gas chromatographic measurement of plasma levels of sodium valproate: tentative treatment of refractory epileptics. Clin Exp Pharmacol Physiol 1978;5 :67-73. 12. Bruni J, Wilder BJ, Willmore LJ , Perchalski RJ, Villarreal HJ. Steady-state kinetics of valproic acid in epileptic patients. Clin Pharmacol Ther 1978;24: 324-32. 13. Gram L, Flachs H, Wiirtz-J.prgensen A, Parnas J, Andersen B. Sodium valproate, serum level and clinical effect in epilepsy: a controlled study. Epi/epsia 1979;20: 303-12. 14. Fukuyama Y. Borderland of childhood epilepsy, with special references to febrile convulsion and so-called infantile convulsion (in Japanese). Seishin Igaku (Tokyo) 1963;5 :211-23. 15. Anonym. Sodium valproate: A new anticonvulsant. Med Lett Drugs Ther 1977;19:93-4 . 16. LeBihan G, Bourreille J, Sampson M, Leroy J, Szekely AM, Coquerel A. Fatal hepatic failure and sodium valproate. Lancet 1980;2: 1298-9. 17. Gerber N. Dickinson RG, Harland RC, et al. Reye-like syndrome associated with valproic acid therapy. J Pediatr 1979; 95: 142-4. 18. Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. J Pediatr 1981; 99: 317 -9. 19. Kanayama M, Sugiyama N, Morishita H, Ishikawa T , Wada Y, Akiyama T. Effects of valproate on mitochondrial function in epileptic patients (in Japanese). No To Hattatsu (Tokyo) 1985;17:507-13. 20. Hayasaka K, Takahashi I, Kobayashi Y, Iinuma K, Narisawa K, Tada K. Effects of valproate on biogenesis and function of liver mitochondria. Neurology 1986;36: 351-6. 21. Sackellares JC, Sato S, Dreifuss FE, Penry JK. Reduction of steady-state valproate levels by other antiepileptic drugs. Epilepsia 1981;22:437-41.
22. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and poly therapy. Epi/epsia 1982;23:693-720. 23. Levy RH. Variability in level-dose ratio of valproate: monotherapy versus poly therapy. Epi/epsia 1984;25 (Suppl I): S 10-3. 24. Cloyd JC, Kriel RL, Fischer JH. Valproic acid pharmacokinetics in children. II. Discontinuation of concomitant antiepileptic drug therapy. Neurology 1985;35: 1623-7. 25. Pinder RM, Brogden RN, Speight TM, Avery GS. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 1977;13:81-123. 26. Chun AHC, Hoffman OJ, Friedmann N, Carrigan PJ. Bioavailability of valproic acid under fasting! nonfasting regimens. J Clin Pharmacol 1980;20: 30-6. 27. Ishikawa T, Horie M, Furuyama M, et al. Bioavailability of a film-coated tablet of valproate in nonfasting volunteers. Jpn J Psychiatr Neurol 1987 ;41(accepted). 28. Braun SL, Tausch A, Vogt W, Jacob K, Knedel M. Evaluation of a new valproic acid enzyme immunoassay and comparison with a capillary gas-chromatographic method . Clin Chem 1981;27: 169-72. 29. Kumps AH, Jumps-Grandjean B, Mardens Y. Enzyme immunoassay and gas liquid chromatography compared for determination of valproic acid in serum. Clin Chem 1981 ;27: 1788-9. 30. Farrell K, Abbott FS, Orr JM , Applegarth DA , Jan JE , Wong PK. Free and total serum valproate concentrations: Their relationship to seizure control, liver enzymes and plasma ammonia in children. Can J Neurol Sci 1986;13:252-5. 31. Sugie Y, Kitahara H, Sugie H, Fukuyama Y. Clinical and electroencephalographical effects of sodium valproate against epileptic convulsions (in Japanese). No To Hattatsu (Tokyo) 1981;13:352-60. 32. Masubuchi Y. A prospective study of sodium valproate monotherapy in untreated epileptic patients: serum concentrations and clinical effects (in Japanese). Tenkan Kenkyu (Tokyo) 1985;3:1-10.
Ishikawa et af: VPA concentrations in epilepsy
287
The lower limits of the "therapeutic range" for serum levels of sodium valproate (VPA) were evaluated in epileptic children showing a benign clinical course. Twenty-five outpatients, aged 5 to 16 years, whose seizures were well controlled over three years with VPA alone, were studied. Venous blood was taken 1.1 to 5 hrs after the morning dose. Serum VPA concentrations at steady-state after receiving the maintenance doses to control seizures were determined by enzyme immunoassay. The patients were divided into three groups according to the seizure type and the age at onset; A and B: patients with tonic and/or clonic seizures, aged below 3 yrs (n = 11) and 3 to 11 yrs (n = 6), respectively, C: those with absence seizures, aged 4 to 11 yrs (n = 8). The serum concentrations in A (47.8 ± 21.6 pg/ml, mean ± SD) were significantly (p < 0.02) lower than those in groups Band C (85.2 ± 14.0 and 73.0 ± 17.4 pg/ml, respectively). VPA concentrations below 50 pg/ml were seen in 6 patients (55%) in group A. It was concluded that many epileptic children, whose ages at onset were below 3 yrs, with tonic and/or clonic seizures could be controlled even with low initial serum concentrations below the "therapeutic range". Key words: Valproate, antiepi/eptic drug, therapeutic range, serum concentration, therapeutic drug monitoring, monotherapy, epilepsy, tonic-clonic seizure, absence seizure. Ishikawa T, Ogino C, Furuyama M, Kanayama M, Awaya A, Yamaguchi A. Serum valproate concentrations in epileptic children with favourable responses. Brain Dev 1987; 9: 283-7
Although sodium valproate (VP A) is a widely used antiepileptic drug [1], the "therapeutic range" remains controversial because of the variety of its adverse effects in epileptic patients [2-4]. In recently published textbooks, authors [5-8] describe the "therapeutic range" of 50 to 100 pg/ml in patients, except for the low recommended dose mentioned in Menkes' textbook [9]. But the previous studies cited in the textbooks have been confined to the intractable epileptic patient samples on polypharmacy [10-13]; nevertheless, the "therapeutic range (50-100 pg/ml)" seems to be uniformly used in practice without consideration of the severity of the epileptogenesis. Therefore, we evaluated the lower limit of the "therapeutic range" for VPA, with regard to the age at onset and the seizure type, in epileptic children showing a
From the Department of Pediatrics, Nagoya City University Medical School, Nagoya. Received for pUblication: August 8, 1986. Accepted for publication: November 14, 1986. Correspondence address: Dr. Tatsuya Ishikawa, Department of Pediatrics, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan.
benign clinical course after starting VPA monotherapy.
SUBJECTS AND METHODS The table shows the characteristics of our subjects, who were 25 previously untreated epileptic outpatients attending Nagoya City University Hospital from 1975 to 1982. The patients received VPA (Depakene®, Kyowa Hakko Co Ltd) monotherapy and they were followed at one month intervals, and at each visit the occurrence of seizures was recorded. Their seizures were well controlled over 3.5 years and the present ages (July 1986) ranged from 5 to 16 yrs (mean 11.4). VP A was administered regularly either in solution (patients 1-4, 6-11, 17) or film-coated tablets (patients 5, 12-16, 18-25) in three divided doses. Venous blood was taken at 1.1 to 5.0 hours (Fig 1) after the morning dose following breakfast. Serum VP A concentrations at steadystate after receiving the maintenance doses to control seizures were determined by the homogeneous enzyme immunoassay (EMIT®, Daiichi Kagaku Yakuhin Co Ltd). The patients were divided into three groups according to the age at onset and the seizure type (Table): A and B: patients with tonic and/or clonic seizures, aged below 3 yrs (patients 1-11) and 3 to 11 yrs (patients 12-17),
Table I Characteristics of 25 patients seizure-free over three years Groupa A
Patient/Sex /Age (yrs)
Age at onset (yrs)
Type of epilepsyC
Duration of therapy (yrs)
Follow-up EEGd
* 3
Tonic
SGE
3-
2/F / 10
* 5
Clonic
PGE
4-
3/M/ 5
* 3
Tonic-clonic
PGE
1- 3
E
* 4
Tonic-clonic
PGE
1-
G
* 5
Tonic
PGE
6-12
E
0/ 12
* :3
Tonic
UGE
8-
G
7/ M/ 9
2
* 7
Tonic
PGE
4-
F
8/M/ 8
2
* 5
Tonic
UGE
3- 7
E
9/M/ 5
2
2-
G
3- 6
E
4/F/ 5 6/M/15
8/ 12
10/M/ 7 I1 /F/ 6
C
Seizure type
I/ F/ 7
5/ F/ 12
B
Total seizure frequencyb
7/ 12
Tonic-clonic
PGE or IC
* 5
Tonic
PGE
>10
Tonic-clonic
SGE
:3
7/12-
MR; VSD
G
12/F/ 15
6
6
Clonic
PGE
6-14
E
13/F/ 15
11
* 5
Clonic
UGE
11-15
E
14/F/ 15
11
* 2
Tonic
PE (BECCT)
11-
F
15/M/16
10
3
Atonic
PE
12-
F
16/M/ 15
9
* 3
Clonic
PE
10-
F
17 /F / 8
3
* 3
Tonic
PE
3-
G
18/M/ 14
4
Frequent
Absence
PGE
7-12
E
19/F/15
8
Frequent
Absence
PGE
8-
G
20/F/ 13
8
*Frequent
Absence
PGE
9-
F
21 /F/ 12
8
*Frequent
Absence
PGE
8-
F
22/ M/ I0
4
*Frequent
Absence
PGE
5-
F E
23/F/ 15
8
Frequent
Absence
PGE
9-14
24/F/I O
4
Frequent
Absence
PGE
5-
25 /F/ 15
11
*Frequent
Absence
PGE
12-
Remarks e
MR (IQ 40, WlSC-R) Mental subnormality (lQ 74 , WISC)
MR (lQ 64, TanakaBinet)
F
a: Groups A and B: patients with tonic and/or clonic szs, aged below 3 yrs and 3 to II yrs, respectively, group C: those with absence szs, aged 4 to II yrs. b: Asterisk: no clinical szs after starting the therapy . c: SGE: secondary generalized epilepsy, PGE : primary generalized epilepsy, UGE: undetermined generalized epilepsy, IC: so-called infantile convulsion [14), PE : partial epilepsy, BECCT: benign epilepsy of children with centro-temporal EEG foci. d: E: excellent (no epileptic sz discharges on EEG recording for long periods of time and VPA could be stopped), G: good (no epileptic sz discharges on EEG over two years and VPA could be decreased) , F: fair (no epileptic sz discharges on EEG over two years). e: MR : mental retardation, VSD: ventricular septal defect, IQ : intelligence quotient, WISC : Wechsler intelligence scale for children.
respectively, C: those with absence seizures, aged 4 to 11 yrs (patients 18-25). Seventeen patients (9 in A, 4 in Band 4 in C) experienced no clinical seizures after starting the treatment. Therefore, their initial VP A doses (8.319.0 mg/kg/ day, mean ± SD 13.6 ± 3.4 mg/kg/ day) were maintained. The duration of therapy ranged from 2 to 7 yrs in A, from 4 to 8 yrs in B and from 3 to 6 yrs in C. Electroencephalography (EEG) was performed once per year. Twenty-two patients had no epileptic seizure discharges on the EEG recording over 2 yrs. Eight patients,4 in A (patients 3,5,8, 10),2 in B (patients 12, 13) and 2 in C (patients 18, 23), showed excellent EEG
284 Brain & Development, Vol 9, No 3, 1987
responses for long periods of time and VP A therapy could eventually be stopped (Table).
RESULTS Fig 2 shows the daily doses for the three groups: A, 8.330.5 mg/kg; B, 10.8-22.l mg/kg; and C, 8.3-27 .9 mg/kg. No statistical difference in the daily dose was noted among the three groups. Fig 3 shows the serum concentrations for the three groups: A, 18.0-84.4 pgjrnl; B, 67.7-100.0 pgjml; and C, 51.7-104.4pg/ml. The serum concentrations in group A
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Fig 3 The serum valproate concentrations of the three groups according to the age at onset and the seizure type; A and B: patients with tonic and/or clonic seizures, aged below 3 yrs and 3-11 yrs, respectively, C: those with absence seizures, aged 4-11 yrs. Closed circles: patients who could be maintained on initial doses. The concentrations in group A were significantly lower than those in groups Band C (p < 0.02).
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Fig 2 The daily valproate dose of the three groups according to the age at onset and the seizure type; A and B: patients with tonic and/or clonic seizures, onset < 3 yrs (n = 11) and 3-11 yrs (n = 6), respectively, C: those with absence seizures, onset 4-11 yrs (n =8). Oosed circles indicate patients who experienced no clinical seizures after starting the treatment, open circles indicate those who received more than the initial dose.
Ishikawa et al: VPA concentrations in epilepsy 285
were significantly lower than those in groups Band C (p < 0.02, Student's t test). The level/dose ratio (pg/ml/mg/ kg/day) ranged l.53-6.22 (mean 3.53) in A, 3.19-7.14 (mean 5.37) in Band 2.93-6.23 (mean 4.16) in C. VPA concentrations below the "therapeutic range (50-100 Jlg/ ml)" were found in 6 patients (55%, patients 2,4, 7, 8, 10, 11) in group A, and the concentrations ranged 18.047.0 Jlg/ml . All of 6 patients had had VPA in solution and the interval of time after which the samples had been taken was from 1.4 to 4.25 hours (2.5,1.4,3 .9,4.2,2.0 and 4.3 hrs in patients 2, 4, 7, 8, 10 and 11, respectively). None of 14 patients in group Band C, on the other hand, showed VPA concentrations below the "therapeutic range". There was a significant difference in the number of patients who showed serum VPA concentrations below the "therapeutic range" among group A and groups Band C (p
DISCUSSION Since 1977, fatal hepatic failure [15,16], Reye-like syndrome [17] and hyperammonemia [18] are well known as serious adverse effects of VPA. Recently, the effects of VPA on mitochondrial function have been noted [19, 20]. As for the "therapeutic range" for VPA, many textbooks showed the data derived from the studies published before 1979 [10-13], when few serious adverse effects of VPA were distinct [15] . Therefore, it is necessary to reevaluate the "therapeutic range" for VPA therapy. From the following reasons, we chose the patients with well controlled epilepsy who received VPA monotherapy, and the time of blood sampling from 1.1 to 5 hrs after the morning dose . Most previous studies on the "therapeutic range" have been confined to intractable epileptic patient samples on polypharmacy [10-13]. The study of the therapeutic range of the patients with monopharmacy is, however, more precise than that of the patients with polypharmacy because the interaction between VPA and other antiepileptic drugs significantly affects VPA pharmacokinetics [21-24]. There is a wide spectrum of prognosis in epilepsies, from severe ones such as the Lennox-Gastaut syndrome to benign ones such as primary generalized epilepsy, the former being in the minority [5, 6]. Hence, it is difficult to regard the "therapeutic range" for the severe epileptic groups as representative of all epileptic groups. The time of blood sampling is important, since the half-life of VP A is short [25]. VP A attains maximum concentrations (Cmax) in the serum around 3 (in liquid form) [26] or 2-4 (in mm-coated tablet of Depakene®) hrs after ingestion following meals [27] . Therefore in this study of 10 serum samples in group A, at least, the concentrations would be Cmax. For re-evaluating the lower limit of the "therapeutic range", Cmax is preferable to the minimum
286 Brain & Development, Vol 9, No 3,1987
concentration (Cmin), although several investigators [11, 13] took blood samples before the morning dose (Cmin). In preveous studies [10-13], serum VPA concentrations have been determined by gas chromatography (GC). Homogeneous enzyme immunoassay, which showed good correlation to GC [28] or gave even higher values [29 , 30], was used for the determination of serum VPA concentrations in this study. In our series, most epileptic children, whose ages at onset were below 3 yrs, with tonic and/or clonic seizures (group A) have been controlled with low initial serum concentrations (mean: 47.8 Jlg/ml) below the "therapeutic range". Furthermore, it is likely that 9 patients (82%) in group A could be controlled with even if Cmax was lower, since these children experienced no clinical seizures after starting the therapy. Loiseau recommended a change in the recommended daily dose for VPA in France, and stressed that many patients could be stabilized with low serum concentrations below the so-called therapeutic range [1]. A few authors also described epileptic patients who were controlled with low serum VPA concentrations [31, 32]. In regard to the severity of epileptogenesis, the "therapeutic range (50-100 Jlg/ml)" should be updated, considering possible adverse effects. ACKNOWLEDGMENTS We are grateful for the invaluable contributions of our colleagues, Drs. Kuniju Shimizu, Mikiko Nakazato, Rieko Imanishi, Masumi Noda, Naoko Maki, Michiko Esaki and Hiroe Kawade. We wish to thank Kyowa Hakko Co. Ltd. for the determination of serum VPA concentrations. We are also grateful to Misses Yukari Ito , Akiko Ishihara and Kaori Kato for their expert secretarial assistance in the preparation of the manuscript. The contents of this paper were partly reported at the 28th Annual Meeting of the Japanese Society of Child Neurology , Matsue, 1986. REFERENCES 1. Loiseau P. Rational use of valproate: indications and drug regimen in epilepsy. Epilepsia 1984;25 (Suppll) :S6S-72 . 2. Dreifuss FE. Sodium valproate: a reappraisal. In: Pedley TA , Meldrum BS, eds. Recent advances in epilepsy. Edinburgh: Churchill Livingstone, 1983: 35-46. 3. Schmidt D. Adverse effects of valproate. Epilepsia 1984;25 (Suppll):S44-9. 4. Jeavons PM. Non-dose-related side effects of valproate. Epilepsia 1984;25 (Suppll):SSO-S. 5. Loiseau P, Jallon P. Les epilepsies. Paris: Masson , 1981:243. 6. Farmer TW, Greenwood RS. Paroxysmal disordres. In: Farmer TW, ed. Pediatric neurology. 3rd ed. Philadelphia: Harper & Row, 1983:205-63. 7. Miura H. Therapeutic drug monitoring and practical antiepileptic drug therapy (2). In: Akimoto H, Yamauchi T, eds. Textbook of epileptology (in Japanese) . Tokyo: Iwasaki Gakujutsu, 1984: 301-27 . 8. Miura H. Biochemistry and clinico-pharmacological properties of antiepileptic drugs. In: Arima M, Kamoshita S, Suzuki Y, Seki T, Fukuyama Y, eds. New encyclopedia of pediatrics and related medical sciences 13E. Pediatric neurology V (in Japanese). Tokyo: Nakayama, 1985:221-43.
9. Menkes JH. Textbook of child neurology. 3rd ed. Philadelphia: Lea & Febiger, 1985:639 . 10. Schobben F, van der Kleijn E, Gabreels FJM. Pharmacokinetics of Di-N-propylacetate in epileptic patients. Eur J Clin Pharmacol 1975;8:97-105. 11. Vajda FJE, Drummer OH, Morris PM, McNeil 11, Bladin PF. Gas chromatographic measurement of plasma levels of sodium valproate: tentative treatment of refractory epileptics. Clin Exp Pharmacol Physiol 1978;5 :67-73. 12. Bruni J, Wilder BJ, Willmore LJ , Perchalski RJ, Villarreal HJ. Steady-state kinetics of valproic acid in epileptic patients. Clin Pharmacol Ther 1978;24: 324-32. 13. Gram L, Flachs H, Wiirtz-J.prgensen A, Parnas J, Andersen B. Sodium valproate, serum level and clinical effect in epilepsy: a controlled study. Epi/epsia 1979;20: 303-12. 14. Fukuyama Y. Borderland of childhood epilepsy, with special references to febrile convulsion and so-called infantile convulsion (in Japanese). Seishin Igaku (Tokyo) 1963;5 :211-23. 15. Anonym. Sodium valproate: A new anticonvulsant. Med Lett Drugs Ther 1977;19:93-4 . 16. LeBihan G, Bourreille J, Sampson M, Leroy J, Szekely AM, Coquerel A. Fatal hepatic failure and sodium valproate. Lancet 1980;2: 1298-9. 17. Gerber N. Dickinson RG, Harland RC, et al. Reye-like syndrome associated with valproic acid therapy. J Pediatr 1979; 95: 142-4. 18. Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. J Pediatr 1981; 99: 317 -9. 19. Kanayama M, Sugiyama N, Morishita H, Ishikawa T , Wada Y, Akiyama T. Effects of valproate on mitochondrial function in epileptic patients (in Japanese). No To Hattatsu (Tokyo) 1985;17:507-13. 20. Hayasaka K, Takahashi I, Kobayashi Y, Iinuma K, Narisawa K, Tada K. Effects of valproate on biogenesis and function of liver mitochondria. Neurology 1986;36: 351-6. 21. Sackellares JC, Sato S, Dreifuss FE, Penry JK. Reduction of steady-state valproate levels by other antiepileptic drugs. Epilepsia 1981;22:437-41.
22. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and poly therapy. Epi/epsia 1982;23:693-720. 23. Levy RH. Variability in level-dose ratio of valproate: monotherapy versus poly therapy. Epi/epsia 1984;25 (Suppl I): S 10-3. 24. Cloyd JC, Kriel RL, Fischer JH. Valproic acid pharmacokinetics in children. II. Discontinuation of concomitant antiepileptic drug therapy. Neurology 1985;35: 1623-7. 25. Pinder RM, Brogden RN, Speight TM, Avery GS. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 1977;13:81-123. 26. Chun AHC, Hoffman OJ, Friedmann N, Carrigan PJ. Bioavailability of valproic acid under fasting! nonfasting regimens. J Clin Pharmacol 1980;20: 30-6. 27. Ishikawa T, Horie M, Furuyama M, et al. Bioavailability of a film-coated tablet of valproate in nonfasting volunteers. Jpn J Psychiatr Neurol 1987 ;41(accepted). 28. Braun SL, Tausch A, Vogt W, Jacob K, Knedel M. Evaluation of a new valproic acid enzyme immunoassay and comparison with a capillary gas-chromatographic method . Clin Chem 1981;27: 169-72. 29. Kumps AH, Jumps-Grandjean B, Mardens Y. Enzyme immunoassay and gas liquid chromatography compared for determination of valproic acid in serum. Clin Chem 1981 ;27: 1788-9. 30. Farrell K, Abbott FS, Orr JM , Applegarth DA , Jan JE , Wong PK. Free and total serum valproate concentrations: Their relationship to seizure control, liver enzymes and plasma ammonia in children. Can J Neurol Sci 1986;13:252-5. 31. Sugie Y, Kitahara H, Sugie H, Fukuyama Y. Clinical and electroencephalographical effects of sodium valproate against epileptic convulsions (in Japanese). No To Hattatsu (Tokyo) 1981;13:352-60. 32. Masubuchi Y. A prospective study of sodium valproate monotherapy in untreated epileptic patients: serum concentrations and clinical effects (in Japanese). Tenkan Kenkyu (Tokyo) 1985;3:1-10.
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