Epilepsy & Behavior 8 (2006) 391–396

www.elsevier.com/locate/yebeh

Every-12-hour administration of extended-release divalproex

in patients with epilepsy: Impact on plasma
valproic acid concentrations
Ronald C. Reed *, Sandeep Dutta, John H. Cavanaugh, Charles Locke,
G. Richard Granneman
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA

Received 1 August 2005; revised 30 November 2005; accepted 9 December 2005

Abstract

Extended-release divalproex sodium (divalproex-ER) biopharmaceutics after every-12-hour (q12h) administration was compared with
that of once-daily divalproex-ER and conventional divalproex given every 6 hours (q6h) in a multiple-dose (14-day), randomized, three-
period crossover design study in 24 patients with epilepsy concomitantly receiving enzyme-inducing antiepileptic medication(s). Plasma
valproic acid (VPA) minimum concentration (Cmin) for divalproex-ER q12h was higher than the once-daily divalproex-ER Cmin
(P = 0.043). Once-daily divalproex-ER Cmin values were not different from those for divalproex q6h, suggesting that adequate trough
steady-state concentrations are maintained with once daily dosing, despite enzyme-inducing comedication. The degree of peak–trough
fluctuation (DFL, calculated as (Cmax Cmin)/Cavg) in VPA concentration was less with both q12h (35.2% less) and once-daily
(16.9% less) divalproex-ER regimens compared with q6h divalproex (P 6 0.024). The DFL for divalproex-ER dosed as a q12h regimen
was 22% less than that for once-daily divalproex-ER (P = 0.02). The DFL in VPA concentration with divalproex-ER can be minimized
with once-daily administration and more so with q12h administration, compared with conventional enteric-coated divalproex taken q6h.
Ó 2006 Published by Elsevier Inc.

Keywords: Extended-release divalproex; Valproic acid concentrations; Degree of fluctuation; Dosing frequency; Epilepsy patients

1. Introduction Once-daily dosing is certainly a rational option in

The conventional enteric-coated, delayed-release dival-
proex sodium tablet (Depakote, Abbott Laboratories,
Abbott Park, IL, USA; divalproex) is well known in the
treatment of epilepsy. Extended-release divalproex sodium
(Depakote ER, Abbott Laboratories; divalproex-ER) is
specifically engineered for slow release over 22 hours [1],
thus exhibiting a smoother plasma valproic acid (VPA) con-
centration–time profile; it has been approved for once-daily
dosing in epilepsy [2–4]. Once-daily dosing with divalproex-
ER has been shown to significantly reduce tremor, weight
gain, and gastrointestinal complaints, thought to be related
to peak plasma VPA concentrations [5–7].
*
Corresponding author. Fax: +1 847 938 1629.
E-mail address: ronald.reed@abbott.com (R.C. Reed).
patients receiving divalproex-ER, especially for those
receiving it as monotherapy. Yet, some clinicians may
choose to prescribe divalproex-ER every 12 hours, particu-
larly for those patients receiving it as adjunctive therapy
with other antiepileptic drugs (AEDs) commonly given
every 12 hours (e.g., lamotrigine, carbamazepine, topira-
mate, levetiracetam, tiagabine). Keeping dosing instruc-
tions simple for the patient is key to full medication
compliance. As such, instructing patients to take divalpro-
ex-ER once daily and their other AEDs multiple times a
day may be confusing and could result in medication errors.
A simulation study predicted that every-12-hour dival-
proex-ER produces less peak–trough fluctuation in plasma
VPA concentrations compared with once-daily administra-
tion [8]. To date, however, there are no patient data on
the plasma VPA concentration–time profile likely to be

1525-5050/$ - see front matter Ó 2006 Published by Elsevier Inc.

doi:10.1016/j.yebeh.2005.12.004
392 R.C. Reed et al. / Epilepsy & Behavior 8 (2006) 391–396
observed with every-12-hour administration of divalproex-
ER. Our study is the first to examine the impact of every-
12-hour administration of divalproex-ER on the plasma
VPA concentration–time profile and the degree of peak–
trough fluctuation in plasma concentrations compared
with both once-daily divalproex-ER and conventional,
enteric-coated divalproex administered four times a day
in patients with epilepsy receiving enzyme-inducing AEDs
concomitantly.
2. Methods
2.1. Study patients
Twenty-four male and female nonsmoking patients with well-con-
trolled epilepsy were enrolled. Patients had voluntarily signed an
informed consent, which was in compliance with FDA regulations and
approved by the institutional review board prior to performing any
study specific procedures (see Acknowledgments). Patients were concur-
rently receiving divalproex and one of three enzyme-inducing AEDs
(phenytoin, phenobarbital, or carbamazepine) at a stable dose for at
least 4 weeks prior to the start of screening. Patients were required to
be otherwise healthy as assessed by medical history, physical examina-
tion, clinical laboratory evaluation, and a 12-lead electrocardiogram
(ECG). Patients had no clinically significant renal or hepatic impairment
and no history of significant drug hypersensitivity. Patients could not be
receiving any medication on a regular basis (other than divalproex and
phenytoin, phenobaribtal, or carbamazepine) that could not be discon-
tinued during the duration of the study. Patients were excluded from
the study if they had a history of drug and/or alcohol abuse or signif-
icant psychiatric illness or had taken an experimental drug within 30
days prior to start of the study.
2.2. Study design
The study was an open-label, multiple-dose, randomized, three-peri-
od, crossover study comparing three regimens of divalproex sodium
(one enteric-coated and two extended-release formulations) in patients
with epilepsy. After meeting entry criteria, all patients entered a 2-week
dose adjustment period. During this period, patients’ current convention-
al divalproex daily dosages were adjusted to the closest total daily dose
that was divisible by 4 and could be administered using tablets of 250-
or 500-mg dosage strength. Patients received their adjusted total daily
doses of divalproex on an every-12-hour dosage schedule for the remain-
der of the dose adjustment period. On Study Day 1, patients were ran-
domly divided into groups of equal size, and assigned to receive the
following three regimens in a complete crossover fashion: (A) divalpro-
ex-ER, once daily (qd) in the morning, with the single dose equal to
the patient’s total daily dose of conventional divalproex established in
the dose adjustment period; (B) divalproex-ER every 12 hours (q12h),
with each dose equal to half of the patient’s total daily dose of conven-
tional divalproex established in the dose adjustment period; and (C)
conventional divalproex every 6 hours (q6h), with each dose equal to
one-fourth of the patient’s total daily dose of conventional divalproex
from the dose adjustment period. Patients received each regimen for 14
consecutive days without any washout periods. All doses were taken oral-
ly with 120 mL of water under nonfasting conditions, approximately a
half-hour after a meal. Patients also continued to receive the same dose
of their usual regimen, including phenytoin, phenobarbital, or carbamaz-
epine. On the first day of each regimen, patients were given a bottle con-
taining enough of the medication to last 14 days. After taking the first
dose in the morning at 6:00 AM, patients were discharged from the study
center. All patients were required to return the evening of Day 12 of each
regimen for admission to the research center, and were confined until the
morning of Study Day 15 of that regimen.
2.3. Blood samples
Seventeen 7-mL blood samples each were collected by venipuncture on
Study Days 14, 28, and 42 into heparinized vacutainers just prior to morning
dosing (0 hour) and at 1.5, 3, 4.5, 6, 7.5, 9, 10.5, 12, 13.5, 15, 16.5, 18, 19.5, 21,
22.5, and 24 hours after the 6:00 AM dose. Samples scheduled at the same time
as a dose were drawn just before the dosing. In addition, a 7-mL blood sam-
ple was collected from each patient just prior to the 6:00 AM dosing on Study
Days 13, 27, and 41 for determinations of total VPA predose concentrations
(CPD) to ascertain whether or not steady state had been achieved. The plas-
ma samples were analyzed for total VPA concentration using a previously
described, validated gas chromatographic method with flame ionization
detection, with a coefficient of variation of 13.8% [9].
2.4. Pharmacokinetic and statistical analyses
The following VPA pharmacokinetic variables were determined for the
last 24 hours (Day 14) of each regimen using standard noncompartmental
methods [10]: maximum observed plasma concentration (Cmax), time to
observed Cmax (Tmax), minimum observed concentration (Cmin), area
under the concentration-versus-time curve (AUC) calculated by the trap-
ezoidal rule, morning predose concentration (CPD), and degree of peak–
trough fluctuation (DFL = (Cmax Cmin)/Cavg, a unitless measure, where
Cavg is the AUC divided by 24 hours). A series of analyses of variance
(ANOVAs) were performed for Cmin, CPD, logarithm of Cmax, logarithm
of AUC24, and DFL. The initial model contained effects for other AED
(phenytoin, phenobarbitol, or carbamazepine), subject nested within other
AED, period, regimen, carryover of regimen of the preceding period,
interaction of period with other AED, and interaction of regimen with
other AED. The interaction terms and the carryover effects were found
to be unimportant, being removed from the model one at a time by a test
at significance level 0.05, with most of the P values well above 0.05. Thus,
the final model had effects for other AED, subject nested within other
AED, period, and regimen. Within the framework of this model the
regimens were compared pairwise, with each comparison conducted at a
significance level of 0.05.
3. Results
3.1. Patient demographics and data accountability
Of the 24 patients enrolled in the study, 2 withdrew pre-
maturely for personal reasons and their data were not used
in any statistical analyses. Of the 22 patients who complet-
ed the study, the mean age was 28.0 ± 6.5 yr, the mean
height was 168.9 ± 9.4 cm, and the mean weight was
69.8 ± 13.0 kg. Most patients were in the acceptable range
of weight based on height and frame, according to 1983
Metropolitan Life Insurance height and weight tables.
Twenty patients (including two dropouts) were receiving
total daily doses of carbamazepine ranging from 400 to
1800 mg, two patients were receiving phenytoin, and two
were receiving phenobarbital. Their divalproex daily dose
was either 1000 or 2000 mg, except for one patient who
received 3000 mg; total daily doses of divalproex-ER
matched what had been used for each patient’s divalproex
total daily dose.
3.2. Plasma VPA concentrations
The mean plasma VPA concentration–time profiles for
the last day of each period (Days 14, 28, and 42) are
 R.C. Reed et al. / Epilepsy & Behavior 8 (2006) 391–396 393

3.3. Pharmacokinetic parameters

The morning plasma concentrations (predose samples,

Fig. 1. Average steady-state (Day 14) plasma valproic acid concentrations
obtained for 22 patients with epilepsy on enzyme-inducing antiepileptic
medications after receiving conventional enteric-coated, delayed-release
divalproex sodium tablets (divalproex) and extended-release divalproex
sodium tablets (divalproex-ER, in two different regimens).
illustrated in Fig. 1. Divalproex-ER qd and q12h regimens
exhibited a relatively flat concentration–time profile com-
pared with the divalproex q6h regimen. Divalproex-ER
qd and q12h regimens also exhibited distinct VPA Cmax
and Cmin values. In the divalproex q6h regimen, an initial
drop in VPA concentration was observed after the 6:00
AM dose, as expected, indicating the usual 1- to 2-hour
lag time before absorption of this enteric-coated, delayed-
release tablet begins. Also, the Cmin for this regimen did
not occur in the morning prior to 6:00 AM dosing; rather,
it occurred around Hour 10, 4 hours after the day’s second
dose at noon. It is hard to identify a VPA Cmax after the
second or third daily dose of the divalproex q6h regimen;
the VPA concentration rose sharply several hours after
the fourth (midnight) dose in this regimen. In general, for
all three regimens, nighttime (Hours 12–24) concentrations
were slightly lower than daytime (Hours 0–12) concentra-
tions, consistent with previous observations of diurnal
variation in plasma VPA concentrations [11].
CPD) measured on Days 13, 14, and 15 of each regimen
were similar (P > 0.05), indicating that steady state was
reached sometime before the 13th day of administration
(data not shown). VPA pharmacokinetic parameters on
the last day of each regimen (Days 14, 28, and 42) are sum-
marized in Table 1. The mean Cmax values were similar for
the divalproex-ER qd and q12h regimens (71.4 and
71.7 mg/L, respectively) and were lower than that obtained
with the divalproex q6h regimen (82.8 mg/L) (P 6 0.0001).
The divalproex-ER q12h mean Cmin was slightly higher
than divalproex-ER qd mean Cmin (P = 0.043). No statisti-
cally significant difference was observed in VPA Cmin val-
ues between divalproex-ER qd and divalproex q6h
regimens. The mean AUC24 values obtained following
the administration of the three regimens were not statisti-
cally distinguishable (Table 1). The bioavailability of dival-
proex-ER qd relative to divalproex q6h (determined in the
framework of the ANOVA for log transformed AUC24)
was 0.944 (P = 0.06), and that for divalproex-ER q12h
relative to divalproex q6h was 0.981.
The mean DFL for both divalproex-ER qd (0.59) and
q12h (0.46) regimens was statistically significantly lower
(16.9%, P = 0.024, and 35.2%, P < 0.001, respectively) com-
pared with the DFL for the divalproex q6h regimen (0.71).
Additionally, the DFL for the divalproex-ER q12h regimen
was statistically significantly lower (22% less) than the DFL
for the divalproex-ER qd regimen (P < 0.02).
3.4. Safety
Nineteen of twenty-four patients reported at least one
treatment-emergent adverse event, most of which were mild
or moderate in severity. No abnormal vital signs or labora-
tory measurements were noted. No definite conclusion can
be drawn regarding differences in the rate of incidence of
adverse events among regimens because of the small num-
ber of patients studied. In this study, no change in seizure

Table 1
Steady-state pharmacokinetic parameters of valproic acid in patients with epilepsy treated concomitantly with enzyme-inducing medications after 14
consecutive days of administration of divalproex sodium extended-release tablets (in two different regimens), compared with conventional divalproex
sodium delayed-release tablets
Cmax (mg/L) Cmin (mg/L) Tmax (h) AUC0–24 (mg Æ h/L) DFL
Regimen A: divalproex ER qd
Mean 71.4a 39.5 10.3 1366 0.59b
± SD 17.5 15.4 5.8 376 0.27
Regimen B: divalproex ER q12h
Mean 71.7a 45.6c 7.0 1418 0.46b
± SD 17.7 14.1 5.3 382 0.16
Regimen C: divalproex q6h
Mean 82.8 41.0 8.8 1440 0.71b
± SD 21.8 14.3 8.0 384 0.20
a
Cmax values for regimens A and B are statistically significantly lower compared with those for regimen C (P 6 0.0001).
b
DFLs for all regimens are different: A versus B (P = 0.02), A versus C (P = 0.024), B versus C (P = 0.0001).
c
Cmin for regimen B is higher than that for regimen A (P = 0.043).
394 R.C. Reed et al. / Epilepsy & Behavior 8 (2006) 391–396
frequency was observed across the three regimens
(although this study was not designed to detect differences
in breakthrough seizure rates).
4. Discussion
Between 20%–50% of patients with epilepsy require
more than one AED for adequate control of seizures [12],
and frequently, a combination of divalproex with another
enzyme-inducing AED is used because of the well-docu-
mented clinical benefit of the combination [13]. The con-
current use of an enzyme-inducing AED(s) with
divalproex markedly enhances plasma VPA clearance
[14–17], necessitating higher divalproex total daily doses,
which, in turn, results in wide DFLs in plasma VPA con-
centrations with the usual q12h administration (unless
more frequent doses are used). A wide DFL in plasma
AED concentrations, associated with high Cmax, with any
conventional-release AED, commonly leads to clinical tox-
icity [18–21]. Extended-release preparations of AEDs (e.g.,
carbamazepine and VPA/divalproex) have been document-
ed to mitigate the incidence or severity of such toxicity,
presumably by blunting Cmax and/or limiting the DFL
[5–7,22–31]. Minimization of clinical toxicity from AEDs
is paramount for maintaining both patient satisfaction
and compliance with a prescribed AED regimen [32], and
the use of extended-release AEDs has been gaining popu-
larity since AED regimens can be simplified [33]. Although
side effects were noted in patients taking divalproex-ER
(either regimen) in our study, the true incidence of such
side effects could not be determined because of the limited
number of patients in the study and the lack of a placebo
control arm for appropriate comparison.
This study reconfirms that total plasma VPA concentra-
tions are maintained throughout a 24-hour period after
once-daily dosing with divalproex-ER [2–4], even in patients
concomitantly taking enzyme-inducing AEDs. Premature
release of the contents of the divalproex-ER tablet did not
occur during chronic administration (no ‘‘dose dumping’’
was observed), as evidenced by the mean VPA concentra-
tion–time profiles (individual patient profiles, not presented
here, did not show evidence of dose dumping) and by the
statistically significantly lower VPA Cmax values for dival-
proex-ER (both regimens) compared with conventional
enteric-coated divalproex. Also, the VPA Cmin did not ‘‘bot-
tom out’’ in patients taking the divalproex-ER tablet formu-
lation qd or q12h. In fact, the Cmin value for divalproex-ER
administered q12h was statistically significantly higher than
that for qd administration. The blunted Cmax values in the
second and third dosing intervals for the divalproex q6h reg-
imen, as seen in Fig. 1, were not surprising and may be
explained by food-induced gastrointestinal and diurnal var-
iation in VPA absorption [34–36].
Our study represents the first prospective, randomized,
controlled study of the impact of q12h dosing of divalpro-
ex-ER on plasma VPA concentrations in patients with epi-
lepsy, compared with an FDA-approved once-daily
regimen of divalproex-ER and conventional enteric-coated
divalproex administered q6h. A main finding in our study
was the statistically significantly lower peak–trough DFL
of 0.46 for divalproex-ER administered q12h, compared
with DFLs for divalproex-ER qd (0.59) and divalproex
q6h (0.71). This represents reductions in DFL of 16.9%
for qd and 35.2% for q12h regimens of divalproex-ER,
respectively, versus divalproex given q6h. The DFL for
q12h divalproex-ER administration was statistically distin-
guishable (22% less) from that for qd administration
(P = 0.02). The DFL is a hybrid parameter that is influ-
enced by a number of variables, including drug dose,
absorption rate, elimination rate, and dosing interval [37].
Although the DFL may not be a value that is intuitively
obvious to clinicians, it does have a practical application.
It essentially defines the ‘‘smoothness’’ of a plasma concen-
tration–time curve; curves with smaller DFLs are more
nearly flat. A constant intravenous infusion of a drug, at
steady state, would theoretically have a DFL of zero (there
is no real Cmax or Cmin or the difference between these values
is close to zero). Theoretically, an AED formulated to
achieve a smaller DFL (i.e., a blunted Cmax and higher Cavg)
could permit a greater amount (mg) of AED to be adminis-
tered over the course of a day with fewer side effects. Addi-
tionally, the DFL may be correlated with side effects, with
higher values suggesting the potential for a greater number
or greater severity of side effects. In particular, the DFL for
conventional-release carbamazepine in enzyme-induced
patients was 0.685, a value (for carbamazepine) associated
with a greater incidence and severity of side effects [18].
For VPA/divalproex dosing, DFL values have not yet been
correlated with greater side effects. Although our present
study was not specifically designed to show better tolerabil-
ity from a reduced DFL with the once-daily divalproex-ER
tablet, at least it is a reasonable probability that conversion
from a conventional to an extended-release formulation
would minimize side effects. Nevertheless, the clinical
impact of q12h dosing of divalproex-ER on side effects
needs to be systematically studied.
Identical total daily milligram doses of divalproex were
used across the three regimens (divalproex q6h, divalproex-
ER qd, and divalproex-ER q12h) in this study. As the
absolute [1] and relative [38] bioavailability of divalproex-
ER is 89%, utilization of an increased divalproex-ER
dosage of 12% (calculated as 1/0.89 = 12.36%) is recom-
mended to compensate for the lesser bioavailability of
divalproex-ER to provide an equivalent exposure (AUC)
over the dosing interval [3,4]. A range of 8–20% dose incre-
ments are commonly used based on limited available dival-
proex-ER tablet strengths [39]. Yet, there have been times
when this recommendation for a proportional 8–20% dos-
age increase has not been automatically followed by inves-
tigators [2,6,7]. In the context of our analysis examining the
impact of q12h divalproex-ER administration on VPA
concentrations, knowledge of the bioavailability of dival-
proex-ER is not crucial to our findings. Our main reported
result is the difference among the DFLs for VPA from the
 R.C. Reed et al. / Epilepsy & Behavior 8 (2006) 391–396
three different divalproex regimens, not the determination
of bioavailability differences between the formulations or
regimens.
Diurnal variation in plasma VPA concentrations has
been noted to occur with multiple daily dosing [35] of
enteric-coated divalproex, as well as with once-daily dival-
proex-ER administration [11]. Our study was not designed
to comprehensively examine diurnal variation in the char-
acteristics of absorption from either conventional divalpro-
ex or the divalproex-ER formulation. Yet, it is possible
that a slight difference might have been noted in the DFLs
obtained for our once-daily divalproex-ER regimen had it
been administered in the evening, rather than in the morn-
ing, as occurred in this study.
It is important to emphasize that our study examined
the impact of strictly controlled ‘‘every-12-hour’’
administration of divalproex-ER on the plasma VPA
concentration–time profile and its corresponding DFL. Cli-
nicians frequently interchange dosing frequency terminolo-
gy; i.e., ‘‘every-12-hour dosing’’ is commonly referred to as
‘‘twice-daily dosing,’’ and vice versa. Twice-daily (‘‘b.i.d.’’)
administration commonly refers to dose administration
times of 9 or 10 AM and 5 or 6 PM in many hospitals and
heath care facilities. It is entirely likely that many patients
whose clinicians specifically instruct them to take certain
medications every 12 hours actually take their medications
in b.i.d. fashion, either knowingly or inadvertently. Con-
ventional b.i.d. administration has irregular dosing inter-
vals, commonly resulting in consecutive dosing intervals
of 8 and 16 hours each, respectively. The irregular dosing
intervals encountered with such b.i.d. administration
would be expected to produce Cmax and Cmin values and
a DFL ratio different from those obtained with a rigid
every-12-hour drug administration. We caution that our
results apply to divalproex-ER administered chronically
on a strict every-12-hour schedule.
Unbound plasma VPA concentrations were not per-
formed in our study. We are aware that for AEDs in gen-
eral, and VPA specifically, it is the non-protein-bound
(unbound or ‘‘free’’) portion that is pharmacologically
active and frequently yields information that is more clini-
cally meaningful than total AED concentrations in situa-
tions where disease(s) changes protein binding. As many
clinicians seem to focus their drug monitoring efforts and
attention on total plasma AED concentrations, we believed
it would be most appropriate to measure only total VPA
levels in our present study.
Divalproex-ER is commonly used as adjunctive AED
therapy in the treatment of epilepsy. When combined with
other AEDs commonly prescribed once daily, e.g., pheno-
barbital or phenytoin extended-release capsules (Dilantin
Kapseals, formerly Parke–Davis, now Pfizer), it seems log-
ical to administer both divalproex-ER and phenytoin once
daily. Yet, because many other AEDs (e.g., lamotrigine,
carbamazepine, topiramate, levetiracetam, tiagabine) are
commonly prescribed every 12 hours, clinicians may
choose to prescribe divalproex-ER concurrently as an
395
every-12-hour regimen, matching the regimen of the other
AED, with the intent of keeping instructions to the patient
as simple as possible, thus aiding compliance. In such cases,
divalproex-ER, although intended to be given and FDA-
approved for once-daily dosing, can be administered every
12 hours, still fulfilling the need for simplification of
patients’ AED regimens. Finally, as a practical matter,
patients on high total daily divalproex-ER doses may
sometimes prefer to split their daily regimen into an
every-12-hour routine to limit the consumption of a large
number of tablets all at once.
Not so surprisingly, this study confirms what conven-
tional pharmacokinetic theory dictates: namely, that more
frequent, evenly time-spaced dosing (of any drug) minimiz-
es the DFL. Nevertheless, the results of this study should
not be interpreted in a manner that encourages the auto-
matic or routine use of every-12-hour dosing of divalpro-
ex-ER, especially because sufficient pharmacokinetic
[1,3,11,38] and steady-state patient (clinical) [2,4–6,33,38–
40] data now exist to support once-daily dosing in patients
with epilepsy. The decision to use once-daily or every-12-
hour therapy with divalproex-ER depends on a variety of
clinical factors already mentioned.
In conclusion, divalproex-ER administered once daily
or every 12 hours to adult patients with epilepsy concur-
rently taking an enzyme-inducing AED maintains plasma
VPA Cmin values, does not display dose dumping, and
reduces the degree of VPA concentration fluctuation
(DFL) compared with the conventional enteric coated,
delayed-release divalproex sodium tablet given every 6
hours. More importantly, although divalproex-ER is
intended for, and FDA-approved for, once-daily adminis-
tration, it can be given every 12 hours if such a dosing reg-
imen happens to match the regimen of other concomitant
AEDs commonly given on an every-12-hour regimen.
Acknowledgments
The study was conducted at Neurology Associates,
Little Rock, AR, USA, under the supervision of Samuel
Boellner, M.D. This study was sponsored by Abbott
Laboratories.
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