Epilepsy Research (2007) 73, 275—283

journal homepage: www.elsevier.com/locate/epilepsyres

Distinct absorption characteristics of oral

formulations of valproic acid/divalproex
available in the United States
Sandeep Dutta ∗, Ronald C. Reed

Abbott Laboratories, Abbott Park, IL, USA

Received 8 June 2006; received in revised form 8 November 2006; accepted 17 November 2006
Available online 8 January 2007

KEYWORDS Summary Five oral formulations of valproic acid (VPA)/divalproex sodium are approved and
commonly used in the US for treatment of epilepsy, mania/bipolar disorder and migraine pro-
Valproate;
phylaxis. These formulations have unique pharmacokinetic and formulation characteristics
Absorption;
and are designed to treat distinct patient populations. We compared the absorption char-
Pharmacokinetics;
acteristics of all five oral VPA/divalproex formulations currently available in the US. Plasma
Oral formulations;
VPA concentration—time profiles, following single oral dose (250 mg) administration of five
VPA
VPA/divalproex formulations under fasting conditions, from three pharmacokinetic studies in
healthy subjects (N = 9—15 each) were compared. The five VPA/divalproex formulations demon-
strated marked absorption differences. The rate of absorption, as characterized by maximum
concentration (Cmax ) and time to Cmax (Tmax ), may be rank-ordered as: VPA syrup (34.2 mg/L,
0.9 h) > VPA capsule (31.4 mg/L, 2.2 h) > divalproex sodium sprinkle capsule (20.7 mg/L, 4.0 h;
lag-time ∼= 1 h) ∼
= divalproex sodium enteric-coated delayed-release tablet (26.0 mg/L, 3.4 h;
lag-time ∼= 2 h) > divalproex sodium extended-release (divalproex-ER) tablet (11.8 mg/L, 19.7 h).
Divalproex-ER had ∼11% lower exposure (AUC). The comparable AUC across the five formula-
tions, when corrected for bioavailability differences, demonstrates that formulation primarily
affects the drug-release and in vivo absorption of VPA. Only divalproex-ER demonstrated true
sustained-release characteristics.
© 2006 Elsevier B.V. All rights reserved.

Introduction

Five oral formulations of valproic acid (VPA)/divalproex

sodium are approved and commonly used in the United
States for treatment of epilepsy, mania associated with
∗ Corresponding author at: Abbott Laboratories, Department R- bipolar disorder and prophylaxis of migraine headache
4PK, Bldg. AP-13A, 100 Abbott Park Road, Abbott Park, IL 60064- (FDA Orange Book, 2006). These VPA/divalproex formu-
6104, USA. Tel.: +1 847 937 8502; fax: +1 847 938 5193. lations have distinct pharmacokinetic and formulation
E-mail address: [email protected] (S. Dutta). characteristics. The different absorption attributes of

0920-1211/$ — see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2006.11.005
 276
Table 1 VPA/divalproex formulations in the United States

Generic name/formulation type

VPA syrup VPA capsule Divalproex sodium sprinkle Divalproex sodium Divalproex sodium
capsule enteric-coated delayed-release extended-release tablet
tablet

Description
A carboxylic acid designated as A carboxylic acid designated as Divalproex sodium: comprised Divalproex sodium: comprised Divalproex sodium: comprised
2-propylpentanoic acid, also 2-propylpentanoic acid, also of sodium valproate and of sodium valproate and of sodium valproate and
known as dipropylacetic acid or known as dipropylacetic acid valproic acid in a 1:1 molar valproic acid in a 1:1 molar valproic acid in a 1:1 molar
valproic acid (VPA), as the sodium or valproic acid relationship relationship relationship. Once-daily
salt formulation that uses
hydrophilic matrix technology
to control drug release by
erosion of a water-soluble
polymer (hydroxypropylmethyl
cellulose) from the matrix
Clinical benefits
For pediatric, mentally retarded Any condition requiring peak For pediatric, mentally Enteric-coated delayed-release For adolescent (>10 years) and
and elderly patients who are VPA concentration to be retarded and elderly patients formulation that alleviates adults; convenience of once
unable to swallow tablets; attained quickly. Used in who are unable to swallow some GI side effects compared daily dosing; lower peak
commonly administered via cost-driven, controlled tablets. Enteric-coated with VPA syrup and VPA concentrations with reduced
nasogastric tube in ICU patients environments (e.g., particles may alleviate some GI capsules by preventing side effects/improved
(even though an I.V. formulation department of corrections) side effects compared with VPA dissolution and absorption in tolerability compared to
is available); has been used as a syrup and VPA capsules by the stomach divalproex tablets and
retention enema for treatment of preventing dissolution and potentially VPA syrup, VPA
seizures when IV access is limited absorption in the stomach capsules and divalproex
sprinkle capsules
Dosage strengths available
Syrup contains the equivalent of Liquid-filled, soft elastic Hard gelatin capsule contains Delayed-release tablet Extended-release tablet
250 mg valproic acid per 5 mL as capsule contains 250 mg enteric-coated particles of contains divalproex sodium contains divalproex sodium
the sodium salt valproic acid divalproex sodium equivalent equivalent to 125, 250, or equivalent to 250 or 500 mg of
to 125 mg of valproic acid 500 mg of valproic acid. Two valproic acid. Two 250 mg
125 mg tablets are tablets are substitutable for
substitutable for 1 × 250 mg 1 × 500 mg tablet

S. Dutta, R.C. Reed

tablet, and 4 × 125 mg or
2 × 250 mg tablets are
substitutable for 1 × 500 mg
tablet
 Distinct absorption characteristics of valproic acid formulations
Table 1 (Continued )

Generic name/formulation type

VPA syrup VPA capsule Divalproex sodium sprinkle Divalproex sodium Divalproex sodium
capsule enteric-coated delayed-release extended-release tablet
tablet

Dosage and administration

For all dosage forms, the usual initial dosage is 15—20 mg/kg day, increasing by 5—10 mg/kg day every week; upper limit ∼60 mg/kg day
Orally; commonly given as multiple Orally; swallowed without Orally; swallowed whole or Orally; commonly given as Orally, with lower
doses per day chewing to avoid local capsule contents may be multiple doses per day bioavailability (89%) vs.
irritation of the mouth and sprinkled onto any soft food; divalproex tablet, requiring
throat; commonly given as commonly given as multiple dose adjustment of 8%—20%
multiple doses per day doses per day upon conversion from other
formulations; swallowed whole
and should not be crushed,
scored, divided or chewed;
FDA-approved as a once-daily
dose
Indications
Epilepsy Epilepsy Epilepsy Epilepsy, mania and migraine Epilepsy, migraine and mania
Innovator product brand name
Depakene® (2003) Depakene® (2003) Depakote® Sprinkle Capsules Depakote® Tablets (2004) Depakote® ER Tablets (2005)
(2003)
Manufacturers (FDA Orange Book, 2006)
ABBOTT, APOTEX, HIGH TECH ABBOTT, BANNER PHARMACAPS, ABBOTT, no generics ABBOTT, no generics ABBOTT, no generics
PHARMA, MORTON GROVE, PHARM SCHERER RP, USL PHARMA
ASSOC, TEVA PHARMS, UDL
FDA Orange Book lists DEPAKENE FDA Orange Book lists
(ABBOTT) as the reference listed DEPAKENE (ABBOTT) as the RLD
drug (RLD) and the others as AA and the others as AB rated
rated generics generics

277
278 S. Dutta, R.C. Reed

Carrigan et al., 1990

Dutta et al., 2004d

Chun et al., 1980
Reference

Data from generic firms were not available; generic formulations were assumed to be bioequivalent based upon FDA listing in Orange Book as AA- or AB-rated.
fasting), divalproex sodium coated particles in tablet (1 × 250 mg, fasting)b , divalproex
divalproex sprinkle capsule-divalproex sodium coated particles in capsule (2 × 125 mg,

sodium coated particles in tablet (1 × 250 mg, non-fasting)b , and divalproex sodium
VPA syrup (250 mg valproic acid equivalent per 5 mL), VPA capsule (1 × 250 mg, no

divalproex-ER tablet (2 × 250 mg Formulation B, fasting and non-fasting)b , and

divalproex-ER tablet (2 × 250 mg Formulation A, fasting and non-fasting)b ,
enteric coated delayed-release tablet (1 × 250 mg, fasting)

divalproex-ER (1 × 500 mg tablet, fasting and non-fastingb )

diluent)b , and VPA capsule (1 × 250 mg, corn oil diluent)

Plasma concentration values were divided by a factor of ‘‘2’’ to normalize concentration data to a 250 mg dose.
Fasting and non-fasting, 4-period crossover:

Fasting and non-fasting, 3-period crossover:

Figure 1 Comparison of mean plasma VPA concentration—
Fasting, 3—period crossover:
time profiles during absorption phase (panel a) and over 72 h
(panel b) for five oral VPA/divalproex formulations following a
250 mg single dose.

the VPA/divalproex oral formulations produce different

maximum and minimum steady-state total plasma VPA
Study design

concentrations that may lead to clinically meaningful dif-

ferences for patients. For instance, depending on the total
daily dose, dosing frequency and individual patient kinetic
characteristics, peak plasma VPA concentrations that are too
high can increase the number and/or severity of side effects
observed, while a drop below threshold plasma VPA concen-
9
9

10
10

15
N

tration could conceivably be related to breakthrough symp-

toms. Nevertheless, each formulation may have advantages
Single dose (mg)

and limitations—–each is designed to treat and may have a

distinct utility in different patient populations (Table 1).
1 × 500 mgc

Results from these regimens are not reported.

1 × 250 mg
1 × 250 mg

2 × 125 mg
1 × 250 mg

While the absorption characteristics of two of these for-

mulations, enteric-coated and extended-release divalproex
sodium, have been recently delineated (Dutta and Reed,
2006a), the pharmacokinetics of all oral VPA/divalproex for-
mulations currently available in the United States have not
Divalproex sprinkle capsule

been previously compared in a single comprehensive publi-

cation. The purpose of this evaluation was to compare the
Divalproex-ER tablet

absorption characteristics and model the distinct pharma-

Divalproex tablet
Study designs

cokinetic profiles of five oral formulations of VPA that are

VPA/divalproex

commonly used in the United States.

formulationa

VPA capsule
VPA syrup

Methods

Each single-dose, randomized, open-label, single-center study was

Table 2

Study

conducted according to a crossover design in healthy adult subjects.

A washout interval of 7 days separated the doses in each study. The
a
b
c
1

study designs are presented in Table 2. VPA pharmacokinetic param-

Distinct absorption characteristics of valproic acid formulations 279

eters, including maximum observed plasma concentration (Cmax ), oral formulations are presented in Fig. 1a and the entire
time to Cmax (Tmax ), area under the plasma concentration—time pharmacokinetic profiles over 72 h are shown in Fig. 1b.
curve from time 0 to infinity (AUC∞ ), apparent oral clearance While the optimal pharmacokinetic model (chosen from sev-
(CL/F), and apparent volume of distribution (V/F), were calculated eral different models) was fit to the individual subject data
using non-compartmental methods (Gibaldi and Perrier, 1982). for each formulation, for visual illustration of the model pre-
A two-stage modeling approach was utilized to distinguish and
diction, the model fit to the mean data for each formulation
quantify the distinct absorption characteristics of the five VPA for-
mulations. Several mammillary compartmental disposition models
is presented in Fig. 2. The mean pharmacokinetic parame-
(CM) coupled with different absorption models were fit to the ters estimated by compartmental and non-compartmental
observed data using WINNONLIN® (Pharsight, Mountain View, CA): 1 analyses are presented in Table 3. The absolute bioavailabil-
CM with first order absorption model, 2 CM with first order absorp- ity, relative bioavailability, absorption lag time and effect
tion model, 1 CM with first order absorption model and lag-time, 2 of food on bioavailability for the five VPA/divalproex oral
CM with first order absorption model and lag-time, 1 CM with zero- formulations are reported in Table 4.
order absorption model, 2 CM with zero-order absorption model, 3 VPA syrup demonstrated rapid absorption with the high-
CM with zero-order absorption model, 1 CM with multiphasic absorp- est Cmax and shortest Tmax . Although differences were
tion model, 1 CM with Weibull absorption model, and 1 CM with
observed in the rate and extent of VPA absorption among
Double-Weibull absorption model. Initially these pharmacokinetic
formulations in the first 6 h post-dose, in general over the
models were fit to the observed mean concentration—time profiles
to determine the model that optimally characterizes the data for
entire sampling period, the rate and extent of absorp-
each formulation. The optimal model was chosen using the visual tion, as characterized by Cmax , Tmax and AUC (Table 3),
fit of the model to the data, and the Akaike Information Crite- were similar for VPA capsule, divalproex sprinkle capsule,
rion and Schwartz Bayesian Criterion. Subsequently, the optimal and divalproex tablet; but could be rank-ordered as: VPA
models were fit to the individual concentration—time profiles for capsule > divalproex sprinkle capsule ∼ = divalproex tablet.
each formulation. Summary statistics were computed for the model- Divalproex-ER tablet, designed to deliver drug at a slow
estimated pharmacokinetic parameters for each formulation. zero-order rate over more than 18 h (Dutta et al., 2004a),
had the slowest absorption with the lowest Cmax and longest
Tmax .
Results The optimal absorption models (Table 3) were a zero-
order absorption for VPA syrup, first-order absorption for
The comparative mean plasma VPA concentration—time pro- VPA capsule, first-order absorption after a ∼1-h lag-time for
files during the absorption phase for the five VPA/divalproex divalproex sprinkle capsule, and first-order absorption after

Figure 2 Pharmacokinetic model predictions and observed plasma VPA concentration—time profiles over 72 h for five oral
VPA/divalproex formulations following a 250 mg single dose. Symbols and error bars represent mean ± standard deviation. Lines
represent the model fit to the mean data.
 280
Table 3 Mean ± S.D. plasma VPA pharmacokinetic parameters for five distinct VPA/divalproex formulations

VPA/divalproex formulation

VPA syrup VPA capsule Divalproex Divalproex tablet Divalproex-ER tableta

sprinkle capsule

Study number 1 1 2 2 3
Number of subjects 9 9 10 10 15
Reference Chun et al. (1980) Chun et al. (1980) Carrigan et al. Carrigan et al. Dutta et al. (2004d)
(1990) (1990)
Non-compartmental analyses
Cmax (mg/L) 34.2 ± 5.0 31.4 ± 5.0 20.7 ± 2.4 26.0 ± 2.6 11.8 ± 3.0
Tmax (h) 0.9 ± 0.9 2.2 ± 2.4 4.0 ± 1.1 3.4 ± 0.7 19.7 ± 8.2
AUC∞ (mg h/L) 518 ± 100 506 ± 107 485 ± 127 490 ± 133 430 ± 125
CL/F (L/h) 0.50 ± 0.09 0.51 ± 0.10 0.55 ± 0.13 0.54 ± 0.13 0.65 ± 0.29
V/F (L) 8.1 ± 1.4 8.4 ± 1.3 11.8 ± 0.8 11.3 ± 1.2 13.8 ± 5.0
Compartmental analyses
Disposition model 1 CM 1 CM 1 CM 1 CM 1 CM
Absorption parameters k0 = 0.41 ± 0.18 g/h ka = 2.0 ± 2.1 h−1 ka = 1.2 ± 0.42 h−1 ka = 4.1 ± 3.4 h−1 A0 = 0.043 ± 0.036 mg/h mg-dose
Tlag = 1.0 ± 0.19 h Tlag = 2.0 ± 0.85 h Amax = 0.21 ± 0.18 mg/h mg-dose
GT50 = 0.38 ± 0.62 h
SIT50 = 1.4 ± 1.2 h
LIT50 = 25 ± 10 h
␥ = 4.8 ± 3.7
CL/F (L/h) 0.52 ± 0.083 0.52 ± 0.094 0.57 ± 0.13 0.58 ± 0.13 0.67 ± 0.32
V/F (L) 7.1 ± 1.6 7.6 ± 0.85 11 ± 0.68 9.5 ± 1.2 10 ± 4.7
Data expressed as mean ± standard deviation. k0 : zero-order absorption rate, ka : first-order absorption rate, Tlag : absorption lag-time, A0 : zero-order absorption rate, Amax : maximum
absorption rate, GT50 : gastric emptying time; SIT50 : small intestinal transit time, LIT50 : large intestinal transit time, ␥: sigmoidicity.
a Plasma concentration values were divided by a factor of ‘‘2’’ to normalize concentration data to a 250 mg dose.

S. Dutta, R.C. Reed

 Distinct absorption characteristics of valproic acid formulations
Table 4 Absolute bioavailability, relative bioavailability, absorption lag time and effect of food on the pharmacokinetics of five distinct VPA/divalproex formulations

VPA/divalproex Absolute bioavailability (% F) Relative bioavailability (%) Lag time for absorption (h) Effect of food
formulation

VPA syrup ∼100a VPA capsule/VPA syrup = 96 (Chun et None No effect on AUC; Cmax is 18%
al., 1980) lower (Chun et al ., 1980)
Divalproex sprinkle capsule/VPA
syrup = 102 (Cloyd et al., 1992)
VPA capsule ∼95b VPA capsule/VPA syrup = 96 (Chun et None Tmax is delayed; AUC is 4% lower;
al., 1980) Cmax is 27% lower (Chun et al.,
1980)
VPA capsule/divalproex Tablet = 95 Tmax is delayed; no effect on AUC
(Fischer et al., 1988) & Cmax (Fischer et al., 1988)
Divalproex sprinkle capsule ∼99c Divalproex sprinkle 0.5—1 Tmax is delayed; no effect on AUC
capsule/divalproex tablet = 99 and Cmax (Carrigan et al., 1990)
(Carrigan et al., 1990)
Divalproex Sprinkle Capsule/VPA
Syrup = 102 (Cloyd et al., 1992)
Divalproex tablet 100.7 (Hussein et al., 1994) VPA capsule/divalproex tablet = 95 1—2 (followed by rapid absorption, Tmax is delayed; no effect on AUC
(Fischer et al., 1988) with rate ∼
= VPA capsule) or Cmax (Fischer et al., 1988)
Divalproex sprinkle
capsule/divalproex tablet = 99
(Carrigan et al., 1990)
Divalproex-ER tablet 89.6 (Dutta et al., 2004a) Divalproex tablet/divalproex-ER None <10% effect on AUC and <6% on
tablet = 89 (Dutta and Zhang, 2004b) Cmax (Dutta and Reed, 2004c;
Cavanaugh et al., 1997)
a Calculated as VPA syrup/IV = VPA syrup/VPA capsule × VPA capsule/divalproex tablet × divalproex tablet/IV relative and absolute bioavailabilities (Chun et al., 1980; Fischer et al.,

1988; Hussein et al., 1994).

b Calculated as VPA capsule/IV = VPA capsule/divalproex tablet × divalproex tablet/IV relative and absolute bioavailabilities (Fischer et al., 1988; Hussein et al., 1994).
c Calculated as divalproex sprinkle capsule/IV = divalproex sprinkle capsule/divalproex tablet × divalproex tablet/IV relative and absolute bioavailabilities (Carrigan et al., 1990; Hussein

et al., 1994).

281
282 S. Dutta, R.C. Reed

a ∼2-h lag-time for divalproex tablet. Divalproex-ER tablet to achieve comparable plasma exposure (AUC) (Dutta and
absorption had multiple-phases and extended over ∼25 h. Reed, 2004c).
Divalproex-ER tablet absorption was optimally described by The mean exposure (AUC), apparent oral clearance
a previously published multiphasic absorption model charac- (CL/F), and apparent volume of distribution (V/F) were
terized by a peak rate that occurs immediately after dosing comparable for four of five formulations-VPA syrup, VPA
followed by a constant rate observed over ∼25 h (Dutta and capsule, divalproex sprinkle capsule and divalproex tablet.
Reed, 2006b). Divalproex-ER tablet had ∼11% lower AUC, and higher CL/F
A simple one-compartment model was found to be and V/F, due to lower absolute bioavailability (F) compared
optimal for describing the disposition of VPA following with the other four formulations (Table 3).
administration of the five different VPA/divalproex formu- Food had no or minimal effect on the VPA pharmacoki-
lations. The mean CL/F and V/F values were consistent netics for the five formulations (Table 4). The effect of food
across formulations (Table 3): the pharmacokinetic model- on AUC was none or minimal (<10%) for all five formulations,
estimated parameter values ranged over 0.52—0.67 L/h on Cmax was none for all formulations except VPA syrup and
and 7.1—11 L, and the non-compartmental analyses esti- possibly VPA capsule, and Tmax was slightly delayed for VPA
mated parameter values ranged over 0.50—0.65 L/h and capsule, divalproex sprinkle capsule and divalproex tablet.
8.1—13.8 L, respectively. In particular, concomitant food intake does not produce a
‘‘dose dumping’’ effect for once-daily divalproex-ER (Dutta
et al., 2004a).
Discussion For VPA syrup and capsule we have presented data for
Depakene® (ABBOTT) because it is published and is the Ref-
We show here, for the first time, that the five VPA/divalproex erence Listed Drug (i.e., Innovator) per FDA Orange Book.
oral formulations available in the United States demonstrate The generic formulations of branded syrup and capsule
distinct absorption characteristics (both rate and extent). (Depakene® ) listed by the FDA Orange Book are bioequiv-
The rate of absorption, as characterized by Cmax and Tmax , alent according to FDA bioequivalence standards.
may be rank-ordered as: VPA syrup > VPA capsule > divalproex The data presented here are from multiple studies.
sprinkle capsule ∼ = divalproex tablet > divalproex-ER tablet. Although cross-study comparisons have some inherent defi-
Although the extent of absorption is significantly less (89%) ciencies, this comprehensive and quantitative comparison of
for divalproex-ER compared to the other formulations, when all oral VPA/divalproex formulations available in the United
corrected for bioavailability differences, the AUC values States, has clinical and practical utility. The comparative
across the five formulations are comparable, demonstrating absorption characteristics and bioavailability of the five for-
that it is truly the formulation itself that primarily affects mulations need to be confirmed in a single, randomized,
the drug-release and in vivo absorption of VPA. While some complete-crossover pharmacokinetic study.
clinicians anecdotally claim that the divalproex sprinkle cap- In conclusion, five VPA/divalproex oral formulations
sule (with enteric-coated delayed-release particles) or the available in the United States demonstrated marked
enteric-coated delayed-release divalproex tablet formula- absorption differences. The rate of absorption, as char-
tions have sustained-release properties, herein we confirm acterized by Cmax and Tmax , may be rank-ordered
that divalproex-ER tablet is the only formulation exhibiting as: VPA syrup > VPA capsule > divalproex sprinkle cap-
true sustained-release characteristics. sule ∼= divalproex tablet > divalproex-ER tablet. Appropriate
The absolute bioavailability [F] of a formulation is pharmacokinetic models were used to characterize the
defined as the bioavailability (measured as total exposure distinct absorption profiles of the five VPA/divalproex formu-
or area under the plasma concentration—time curve [AUC]) lations. The mean exposure (AUC), apparent oral clearance
relative to intravenous administration where the entire (CL/F), and apparent volume of distribution (V/F) were
dose is available in the plasma. The absolute bioavailabil- comparable for four of five formulations-VPA syrup, VPA
ity (Table 4) of four of five formulations—–VPA syrup, VPA capsule, divalproex sprinkle capsule and divalproex tablet.
capsule, divalproex sprinkle capsule and divalproex tablet—– Divalproex-ER had ∼11% lower AUC, and higher CL/F and
were ∼100% (Chun et al., 1980; Carrigan et al., 1990; Fischer V/F, due to lower absolute bioavailability (F) compared with
et al., 1988; Hussein et al., 1994); divalproex-ER tablet had the other four formulations. The comparable AUC values
a statistically significantly lower absolute bioavailability of across the five formulations, when corrected for bioavail-
89% (Dutta et al., 2004a). ability differences, demonstrate that formulation primarily
The relative bioavailability (Table 4) for four of five affects the drug-release and in vivo absorption of VPA.
formulations-VPA syrup, VPA capsule, divalproex sprinkle Divalproex-ER tablet is the only formulation exhibiting true
capsule and divalproex tablet-were ∼100% when any two sustained-release characteristics.
formulations were compared (Chun et al., 1980; Carrigan
et al., 1990; Fischer et al., 1988). The bioavailability of Acknowledgment
divalproex-ER tablet relative to the divalproex tablet is sta-
tistically significantly lower, 89% (Dutta and Zhang, 2004b).
This study was sponsored by Abbott Laboratories.
Therefore, while switching patients from a VPA syrup, VPA
capsule, divalproex sprinkle capsule or divalproex tablet
regimen to a divalproex-ER tablet regimen, the divalproex- References
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