bioequivalence studies of a new valproic acid delayed-release capsule and divalproex sodium...
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CURRENT MEDICAL RESEARCH AND OPINION�
VOL. 24, NO. 7, 2008, 1869–1876
0300-7995
doi:10.1185/03007990802122735
� 2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted
ORIGINAL ARTICLE
Bioequivalence studies of a newvalproic acid delayed-releasecapsule and divalproex sodiumdelayed-release tabletVandana Garikipati, Dana S. Toops and Qi Fang
Banner Pharmacaps, High Point, NC, USA
Key words: Bioavailability – Delayed-action preparations – Divalproex – Pharmacokinetics –Valproic acid
ABSTRACT
Objective: The study examined relative bioavailability of a
novel valproic acid (VPA) delayed-release (DR) soft gelatin
capsule formulation to divalproex sodium DR tablet under
fasting conditions and the effect of food on the
bioavailability of the VPA DR soft gelatin capsule.
Method: This open-label, randomized three-way
crossover study enrolled 36 healthy non-smoking adult
volunteers. Treatments included a single 500 mg
divalproex sodium DR tablet, fasting; a single 500 mg VPA
DR soft gelatin capsule, fasting; and, a single 500 mg VPA
DR soft gelatin capsule 500 mg, non-fasting. Analysis
of variance was performed on the pharmacokinetic
parameters. The ratio of geometric means and
corresponding 90% confidence intervals (CI) were
calculated on ln-transformed data for the area under the
serum concentration-time curve (mg-hr/mL) from time zero
to the time of the last quantifiable concentration (t)(AUC0–t ), AUC0–1 and maximum plasma concentration
(Cmax). Bioequivalence was shown when 90% CIs were
within the 80–125% range.
Results: All subjects completed the study. The 90% CIs of
VPA DR soft gelatin capsules compared to divalproex
sodium DR tablets were within the 80–125% limits for
AUC0–t, AUC0–1, and Cmax. The time of maximum or peak
concentration (Tmax) of VPA DR soft gelatin capsules was
2.3 hours versus 3.7 hours with divalproex sodium DR
tablets. AUC0–t and AUC0–1 of VPA soft gelatin capsules
were not affected in the non-fasting condition, but Tmax
occurred at 6.1 hours compared to 2.3 hours fasting.
Eight subjects experienced a total of 10 adverse events;
none were serious.
Conclusion: The VPA DR soft gelatin capsule
formulation was shown to be bioequivalent to divalproex
sodium DR tablet and no serious adverse events occurred.
Because this was not a multiple-dose study, however,
direct comparisons in chronic dosing were not possible.
Administration with food affected rate but not extent of
absorption of the VPA DR soft gelatin capsules, but
comparisons with the reference product were not
conducted under non-fasting conditions.
Introduction
Valproate is the active ingredient in a number of
pharmaceutical formulations used to treat bipolar
mania, manage epileptic seizures, and prevent
migraine headaches1. Available injectable and oral
formulations include valproate sodium, valproic
acid, and divalproex sodium (sodium valproate and
valproic acid). These formulations differ in their
pharmacokinetic properties and their specific
Address for correspondence: Vandana Garikipati, Team Lead Clinical Pharmacology, BannerPharmacaps, Inc., 4125 Premier Drive, High Point, NC 27265, USA. Tel.: þ1 336 812 8700;Fax: þ1 336 812 9091; [email protected]
Paper 4449 1869
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approved indications1–3. Pharmacokinetics and dosing
of these formulations have been studied extensively
in various clinical settings4–10.
The valproic acid (VPA) delayed-release soft gelatin
capsule (Stavzor*), the subject of this study, is an,
enteric, delayed-release formulation and is the first
delayed-release soft gelatin capsule formulation of
valproic acid. Soft gelatin capsules are a formulation
in which the drug is present in solution or suspended in
a vehicle. The VPA delayed-release soft gelatin capsule
shell includes an enteric polymer as part of the gelatin
shell that differs from other approved valproic acid
delayed-release products that are enteric-coated
beads or pellets. The capsule shell is resistant to gastric
acid, but it ruptures upon exposure to the intestinal
pH and releases the valproic acid. The capsule fill
contains no excipients other than the active drug.
VPA delayed-release soft gelatin capsule was
developed as an alternative dosage form to current
therapies, such as Depakotey and Depakote ER as
well as the immediate release valproic acid products.
VPA delayed-release enteric soft gelatin capsules
(500 mg) are approximately 40% smaller in size than
divalproex sodium delayed-release tablets11. It has
been shown previously that equivalent oral doses
of valproic acid capsules and divalproex sodium
tablets deliver equivalent quantities of valproate ion
systemically12,13. Following oral administration,
divalproex sodium dissociates rapidly to valproate
ion in the gastrointestinal tract where valproate
ion is rapidly and almost completely absorbed1,12,13.
Valproate undergoes extensive hepatic metabolism
and is eliminated by first order kinetics. Mean
terminal half-life of valproate ion varies and has
been reported to range over 9–16 hours when
administered as monotherapy in dosages from
250 mg to 1000 mg per day12,13.
Administration with or without food can affect
the rate of absorption within and between formula-
tions12. For example, with administration of valproic
acid under fasting conditions, maximum plasma
concentration (Cmax) is usually achieved within
1–4 hours following oral administration. With
divalproex sodium, Cmax is usually reached within
approximately 3–7 hours following oral administra-
tion5,6. Under non-fasting conditions, the time to
Cmax has been shown to be increased from 3.3 to
4.8 hours with Depakote sprinkle capsules and from
4 to 8 hours with divalproex sodium (Depakote
tablets)12. However the bioavailability is not affected
by food14.
Given the pharmacokinetic variability within and
among formulations, a series of studies were designed
to evaluate the pharmacokinetic properties of the VPA
delayed-release soft gelatin capsule in relation to the
divalproex sodium delayed-release tablet. One pilot
study with a single oral dose of VPA delayed-release
soft gelatin capsule, 500 mg administered fasting to
six subjects was conducted to characterize the
pharmacokinetic parameters compared to divalproex
delayed-release tablet, 500 mg15. Although the study
was too small for statistical analysis, the results
indicated that the two formulations were likely to be
bioequivalent. A second pilot study showed that time
to Cmax of the VPA delayed-release soft gelatin
capsule was delayed by food from 2.4 hours under
fasting conditions to 5.0 hours under non-fasting
conditions16. Together, these results suggested that a
full bioequivalence study with a larger sample size was
warranted.
The primary objective of this present study was to
determine the relative bioavailability of VPA delayed-
release soft gelatin capsule (Stavzor), 500 mg, com-
pared to divalproex delayed-release tablet (Depakote),
500 mg following a single oral dose. A secondary
objective was to determine the effects of food on
serum levels of valproic acid following administration
of a single oral dose of a VPA delayed-release
soft gelatin capsule under fasting and non-fasting
conditions. The study was designed to conform to
US Food and Drug Administration (FDA) Guidance
for Industry on Bioavailability and Bioequivalence
Studies for Orally Administered Drug Products –
General Considerations14.
Methods
Design
The study was a randomized, open-label, three-way
crossover design. Investigators and patients were not
blinded; however, the bioanalytical facility was
blinded to the randomization code to prevent bias
during analyses. An enrollment of 36 subjects was
planned. The study was conducted at one site by
PRACS Institute, Ltd, East Grand Forks, North
Dakota, USA. The study was reviewed and approved
by PRACS Institutional Review Board (IRB).
All subjects provided written informed consent to
participate. The study conduct also conformed to the
United States Code of Federal Regulations and
the International Conference on Harmonisation of
*Stavzor is a registered trademark of Banner Pharmacaps, Inc, High Point NC, USA, and Noven Pharmaceuticals, Miami,FL, USAyDepakote and Depakote ER are registered trademarks of Abbott Laboratories, North Chicago, IL, USA
1870 Valproic acid soft gelatin delayed-release capsule � 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(07)
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Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) (United
States Code of Federal Regulations. 21 CFR Part
50 and 56).
Subjects
Healthy, non-smoking, male and non-pregnant female
adult volunteers were eligible to participate. Subjects
were required to be 18 years of age or older and
within �20% of ideal body weight (Table of
Desirable Weights of Adults, 1983 Metropolitan
Height and Weight Table). Exclusion criteria included
hypersensitivity to valproic acid, divalproex sodium
or related drugs, recent history of drug or alcohol
addiction or abuse, positive drug abuse screen, or
reactive screen for hepatitis B surface antigen,
hepatitis C antibody or human immunodeficiency
virus (HIV) antibody. Pregnant or lactating females
were excluded as were subjects with clinically
significant laboratory test values outside the reference
range, use of any drug known to induce or inhibit
hepatic metabolism within the previous 28 days or
participation in an investigational drug study within
the previous 28 days.
Treatments
The study included three randomized treatment
periods (A, B, and C) with a 7-day washout period
between each treatment period. For Treatment A, the
test product was a single 500 mg VPA delayed-release
soft gelatin capsule (Stavzor, Banner Pharmacaps, Inc,
High Point, NC; Noven Pharmaceuticals, Miami,
FL, USA), administered under fasting conditions. For
Treatment B, the test product was also a single 500 mg
VPA delayed-release soft gelatin capsule administered
under non-fasting conditions.
Treatment C, the reference product, was a single
500 mg divalproex sodium delayed-release tablet
(Depakote, Abbott Laboratories, North Chicago,
IL, USA), administered under fasting conditions.
In fasting conditions, the treatments were
administered following a 10-hour pre-dose fast. For
the non-fasting condition, the single 500 mg VPA
delayed-release soft gelatin capsule was administered
30 minutes after initiation of a standardized high fat
breakfast consisting of two eggs fried in butter, two
strips of bacon, two slices of toast with butter,
four ounces of hash brown potatoes, and 240 mL
whole milk. Subjects were required to refrain from
grapefruit, xanthine- and caffeine-containing foods
and alcohol 48 hours prior to dosing and 72 hours
post-dosing.
Procedures
Subjects entered the study center a minimum of 10.5
hours prior to the first dose. A pre-study medical
history and physical examination were conducted
including vital signs, electrocardiogram, complete
blood count with differential, clinical chemistry and
urinalysis. The randomization scheme was computer
generated and subjects were randomized prior to
Period I dose administration.
Dosing procedure
One tablet or capsule was administered with 240 mL
ambient temperature water, followed by an additional
240 mL of ambient temperature water 2 hours
post-dose. Subjects were dosed in groups of three at
1 minute intervals and compliance with administration
of medication was verified visually. Subjects remained
seated in an upright position for 4 hours post-dose and
fasted for 4.25 hours after dosing.
Standardized meals were administered at 4.25, 10.5
and 14.5 hours post-dose. Meals were identical during
all three treatment periods. Water was permitted
ad lib, if requested during periods when fluids were
not restricted. Subjects remained in the study center at
least through the 24-hour post-dose blood sample for
each treatment period. Strenuous activity during the
confinement period was not permitted. Subjects
returned to the study center at 36, 48 and 72 hours
post-dose for blood collection samples.
Blood samples and processing
Venous blood samples were collected by venipuncture
into vacutainer tubes within 1 hour prior to dosing
(time 0), at 30 minute intervals through 6 hours
post-dose, and subsequently at hours 7, 8, 12, 16,
24, 36, 48 and 72 hours post-dosing. Blood samples
were allowed to clot, centrifuged at 4�C for 15 minutes
and the serum pipetted into polypropylene tubes,
frozen and stored at or below –20�C until analysis.
Analytical method
Valproic acid concentrations were determined in
serum using high performance liquid chromatography
with tandem mass spectrometry (LC-MS/MS). The
concentration range of the assay was 2.00 mg/mL to
100.00 mg/mL. Sample values below 2.00mg/mL were
reported as zero. Concentrations of Quality Control
(QC) standards were 6.00 mg/mL for the Low,
50.00 mg/mL for the Mid, 80.00 mg/mL for the High
and 25.00 mg/mL for the Blind. The calibration
standards showed inter-batch accuracy from 98.00%
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to 101.01% with precision from 1.46% to 2.33%. The
coefficient of determination (r2) was at least 0.9985.
Of the 192 QC samples analyzed with the subject
samples in acceptable batch runs, 1 QC (0.5%) failed
the acceptance criteria. Bioanalytical analysis was done
at PRACS Institute, Ltd, Fargo, North Dakota, USA.
Pharmacokinetic measurements
Pharmacokinetic parameters assessed included area
under the serum concentration-time curve (mg-hr/mL)
from time zero to the time of the last quantifiable
concentration (t) (AUC0–t), calculated using the linear
trapezoidal rule; area under the serum concentration-
time curve (mg-hr/mL) from time zero extrapolated to
infinity (AUC0–1), calculated by AUC0–tþ (Clast/ke),
where Clast is the last quantifiable concentration and
ke is the terminal elimination rate constant; maximum
or peak concentration (mg/mL) obtained by inspection
(Cmax); time of maximum or peak concentration
(hours) obtained by inspection (Tmax); terminal
elimination rate constant (1/hour), estimated by
linear regression on the terminal phase of the semi-
logarithmic concentration versus time curve (ke); and,
half life (T½) of the product (hours) calculated
by ln(2)/ke.
Statistical plan
Based on the pilot study work (both fasting and fed),
the sample size determinations were based on
the table by Diletti et al.17,18, approximated by the
selection of the closest values for the mean ratios and
percent coefficient of variation (% CV). The minimum
sample size needed for the ANOVA to detect a
difference between the products with 80% power
were calculated by using SAS output (SAS Version
8.2; SAS Institute, Inc. SAS OnlineDoc, Version 8.
Cary, NC, USA: SAS Institute, Inc., 1999). The
planned sample size was 36 subjects. An analysis of
variance (ANOVA) was performed on each of the
pharmacokinetic parameters. Differences were
deemed statistically significant at the probability level
of 0.05. The 90% confidence interval (CI) about the
ratio of the mean test value to mean reference value
was calculated using the least squares means and
the standard error of the estimate. Geometric means
were calculated from ln-transformed data of the least
squares means for AUC0–1, AUC0–t and Cmax. The
ratio of the geometric means and the corresponding
90% CIs were calculated. Statistical analyses were
conducted using SAS Version 8.2.
For bioequivalence of the reference and test
products to be established, the 90% CIs for the ratios
of their geometric means for the AUC0–t, AUC0–1 and
Cmax had to fall within the 80–125% range. The
determination of the presence or absence of a food
effect on only the test product was assessed in the same
way: The absence of a food effect on bioavailability of
the VPA delayed-release soft gelatin capsule was
deemed to have been established if the 90% CIs for
the ratios of the geometric means for the AUC0–t,
AUC0–1 and Cmax for the test product under fasting
conditions and non-fasting conditions fell within the
80–125% range.
Safety assessments
Physical examination, vital signs, complete blood
count with differential, clinical chemistry and preg-
nancy screen for female subjects were conducted at
baseline and upon exit within 14 days of the last blood
sample. Heart rate and blood pressure were also
measured at 12 and 24 hours after each dose.
Adverse events (AEs) were collected throughout each
study period and upon exit.
Results
Subjects
Thirty-six healthy, non-smoking adult subjects
(30 men and six women) entered and completed the
study. Demographic data are shown in Table 1.
Pharmacokinetic parameters
The pharmacokinetic parameters for the three treat-
ments are shown in Table 2, and mean serum
Table 1. Summary of mean demographic data (�SD)
All subjects (N¼ 36) Males (N¼ 30) Females (N¼ 6)
Age, years 32.1 (�13.7) 28.1 (�11.1) 52.5 (�3.4)
Weight, pounds 172.8 (�23.5) 175.6 (�22.0) 158.7 (�27.4)
Height, inches 69.6 (�3.4) 70.6 (�2.6) 64.7 (�2.4)
BMI 25.1 (�2.9) 24.8 (�2.7) 26.6 (�3.6)
BMI¼body mass index; SD¼ standard deviation
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concentrations are shown in Figure 1. Under fasting
conditions, all pharmacokinetic parameters except
Tmax were similar for divalproex sodium delayed-
release tablet and VPA delayed-release soft gelatin
capsule. Tmax was 2.3 hours with VPA delayed-release
soft gelatin capsule compared to 3.7 hours with
divalproex sodium delayed-release tablet, a difference
of 38%. Under non-fasting conditions, treatment with
VPA delayed-release soft gelatin capsule resulted in
a Cmax of 41.48 mg/mL as compared to 53.77 mg/mL
under fasting conditions. Tmax occurred at 6.1 hours
with VPA delayed-release soft gelatin capsule under
non-fasting conditions compared to 2.3 hours under
fasting conditions. Extent of absorption (AUC0–t and
AUC0–1), however, was not affected by administra-
tion with food.
Table 2. Summary of pharmacokinetic parameters
Parameter Divalproex sodium
delayed-release (fasting)
VPA delayed-release soft
gelatin capsule (fasting)
VPA delayed-release soft
gelatin capsule (non-fasting)
AUC0–t, mg-hr/mL
Mean (SD) 932.18 (181.80) 902.12 (196.26) 865.30 (192.45)
Geometric mean* 916.05 882.90 845.97
AUC0–1, mg-hr/mL
Mean (SD) 1014.78 (197.42) 985.80 (203.41) 947.40 (206.72)
Geometric mean* 997.51 966.67 926.80
Cmax, mg/mL
Mean (SD) 55.40 (7.74) 53.77 (6.73) 41.48 (7.40)
Geometric mean* 54.86 53.35 40.84
Tmax, hours
Mean (SD) 3.67 (1.16) 2.29 (1.22) 6.07 (2.62)
Ke, L/hour
Mean (SD) 0.0471 (0.0105) 0.0474 (0.0092) 0.0477 (0.0096)
T½, hours
Mean (SD) 15.36 (3.17) 15.12 (2.76) 15.08 (2.91)
*Geometric mean calculated from ln-transformed dataAUC¼ area under the serum concentration-time curve; Cmax¼maximum plasma concentration; Ke¼ terminal elimination rate constant;SD¼ standard deviation; T½¼half life; Tmax¼ time of maximum or peak concentration; VPA¼ valproic acid
0
10
20
30
40
50
60
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Time (hours)
Con
cent
ratio
n (µ
g/m
L)
VPA DR softgel capsule (fasting)
VPA DR softgel capsule (non-fasting)Divalproex sodium DR tablet (fasting)
Figure 1. Mean serum concentrations of valproic acid (0–72 hours). DR¼ delayed-release; VPA¼ valproic acid
� 2008 Informa UK - Curr Med Res Opin 2008; 24(07) Valproic acid soft gelatin delayed-release capsule Garikipati et al. 1873
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Bioequivalence: divalproex sodiumdelayed-release tablet versus VPAdelayed-release soft gelatin capsule
The geometric means of the ln-transformed data, ratio
of means and 90% CIs for AUC0–t, AUC0–1, and Cmax,
for divalproex sodium delayed-release tablet and VPA
delayed-release soft gelatin capsule are shown in
Table 3. The 90% CIs about the ratio of VPA
delayed-release soft gelatin capsule (500 mg) to dival-
proex delayed-release tablet (500 mg) are within the
80–125% limits for AUC0–t (90% CI: 94.34, 98.4),
AUC0–1 (90% CI: 94.93, 98.93), and Cmax (90% CI:
93.1, 101.57). The results therefore meet the criteria
for bioequivalence of these two products.
Food effect: VPA delayed-release softgelatin capsules (fasting vs. non-fasting)
Geometric means, ratios, and 90% CIs about the
means for AUC0–t, AUC0–1 and Cmax for VPA
delayed-release soft gelatin capsules under fasting and
non-fasting conditions are shown in Table 4. The 90%
CIs for the ln-transformed data about the ratio of
Treatment B to Treatment A are within the 80–125%
limits for AUC0–t (90% CI: 93.79, 97.89) and AUC0–1
(90% CI: 93.92, 97.87). Cmax (90% CI: 73.29, 79.96),
however, does not fall within the 80–125% limits,
indicating a statistically significant food effect. The
extent of absorption, however, was not affected as
demonstrated by the absence of a demonstrable food
effect on AUC0–t and AUC0–1.
Safety
Eight subjects experienced a total of 10 adverse events
(AEs) during the course of the pivotal study. No
serious AEs were reported. Non-serious AEs were
reported by two subjects (dizziness) during treatment
with the divalproex sodium delayed-release tablet
reference product. Two subjects treated with VPA
delayed-release soft gelatin capsule during fasting
conditions reported three AEs – two headaches and
one nausea. Four subjects treated with VPA delayed-
release soft gelatin capsules reported five AEs during
non-fasting conditions – nausea (1), back pain (2), pain
in extremity (1) and nasopharyngitis (1).
Discussion
The valproic acid delayed-release soft gelatin capsule
(Stavzor) is a new formulation in which enteric soft
gelatin capsules are liquid-filled with valproic acid.
In this study, the 90% CIs about the ratio of VPA
delayed-release soft gelatin capsule fell within the
80–125% limits for AUC0–t, AUC0–1, and Cmax of the
ln-transformed data when administered as a single oral
dose under fasting conditions. VPA delayed-release
Table 4. Relative bioavailability of VPA delayed-release soft gelatin capsule, fasting versus VPA delayed-release
soft gelatin capsule, non-fasting: geometric means*, ratio of means, and 90% CIs
Parameter VPA delayed-release soft
gelatin capsule (fasting)
VPA delayed-release soft
gelatin capsule (non-fasting)
% ratio 90% CI
AUC0–t 882.90 845.97 95.82 (93.79, 97.89)
AUC0–1 966.67 926.80 95.88 (93.92, 97.87)
Cmax, mg/mL 53.35 40.84 76.56 (73.29, 79.96)
*Geometric means calculated from ln-transformed dataAUC¼ area under the serum concentration-time curve; CI¼ confidence interval; Cmax¼maximum plasma concentration;VPA¼ valproic acid
Table 3. Relative bioavailability of divalproex sodium delayed-release tablet versus VPA delayed-release soft
gelatin capsule: geometric means*, ratio of means, and 90% CIs
Parameter Divalproex sodium
delayed-release tablet
VPA delayed-release
soft gelatin capsule
% ratio 90% CI
AUC0–t 916.05 882.90 96.38 (94.34, 98.47)
AUC0–1 997.51 966.67 96.91 (94.93, 98.93)
Cmax, mg/mL 54.86 53.35 97.24 (93.1, 101.57)
*Geometric means calculated from ln-transformed dataAUC¼ area under the serum concentration-time curve; CI¼ confidence interval; VPA¼ valproic acid
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soft gelatin capsule, 500 mg, was thus shown to be
bioequivalent to divalproex sodium delayed-release
tablet, 500 mg. Tmax was achieved 38% faster with
VPA delayed-release soft gelatin capsule than with
divalproex delayed-release tablet – 2.3 hours compared
with 3.7 hours, respectively.
The extent of absorption (AUC0–t, AUC0–1) with
VPA delayed-release soft gelatin capsule 500 mg
administered following a standardized high-fat
breakfast fell within the 80–125% limit of the 90%
CIs of VPA delayed-release soft gelatin capsule under
fasting conditions. The mean time to Cmax during
non-fasting administration was 6.1 hours compared to
2.3 hours under fasting conditions. Maximum plasma
concentration decreased from 53.8mg/mL under
fasting conditions to 41.5 mg/mL under non-fasting
conditions, a decrease of 23%. Non-fasting conditions
did not affect the extent of absorption of VPA delayed-
release soft gelatin capsule, but did reduce the rate of
absorption relative to fasting conditions.
VPA delayed-release soft gelatin capsule gelatin
capsules were well-tolerated with no serious AEs
associated with their administration in the setting of
this study. AEs were consistent with those described in
prescribing information for other forms of valproic
acid and valproate12,13.
The pharmacokinetics of valproate have been
studied extensively in patients and in healthy volun-
teers1. A food effect on the rate of absorption, but not
its extent, is typical, regardless of formulation. This
effect has not been shown to be clinically significant
when dosing is chronic and when steady state condi-
tions are achieved1. The food effect demonstrated in
the present study is consistent with that seen with
other forms of valproic acid and valproate.
This study has several limitations. The study was not
designed as a multiple-dose study to evaluate steady
state plasma concentrations. Consequently, direct
comparisons of plasma concentrations of valproate
between VPA delayed-release soft gelatin capsule and
divalproex sodium delayed-release tablet in chronic
dosing are not possible. In addition, the study did not
compare VPA delayed-release soft gelatin capsule
and divalproex sodium delayed-release tablet under
non-fasting conditions, but a food effect for divalproex
sodium is well-characterized. Such a comparison is
not a requirement when examining bioequivalence
of orally administered drugs14. Under conditions of
chronic administration, the food effect is not consid-
ered to be clinically significant.
This study also was not designed to evaluate the
clinical significance or benefit of the reduced capsule
size. As noted, the VPA delayed-release soft gelatin
500 mg capsule is approximately 40% smaller than the
same strength of divalproex sodium delayed-release
tablet11. It remains to be determined if this will be of
clinical significance to patients. It can be speculated
that the smaller size of the capsule may be preferred
by patients and could perhaps contribute to improved
adherence to the medication. A preference survey
demonstrated that consumers preferred a softgel
formulation to solid oral dosage forms with respect
to perceived ease of swallowing19. The present study,
however, was intended only to compare the bioequi-
valence of the soft gelatin capsule formulation and
divalproex sodium delayed-release tablets and was not
a therapeutic trial. The clinical impact of the soft
gelatin capsule formulation remains to be studied in
controlled trials.
Conclusions
The novel valproic acid delayed-release soft gelatin
capsule formulation was shown to be bioequivalent to
divalproex sodium delayed-release tablets when admi-
nistered under fasting conditions. Time to maximum
plasma concentration occurred at 2.3 hours compared
to 3.7 hours with divalproex delayed-release tablet,
indicating a faster absorption. As with other forms of
valproate, VPA delayed-release soft gelatin capsule
was subject to a food effect, apparent as delayed time
to Cmax (from 2.3 hours to 6.1 hours) and decreased
Cmax in non-fasting versus fasting conditions (40.84 vs.
53.35 mg/mL, respectively). The extent of absorption
(AUC0–1, AUC0–t), however, was not affected. In this
setting, the VPA delayed-release soft gelatin capsule
formulation was well tolerated.
Acknowledgments
Declaration of interest: VG, DST and QF are
employed by Banner Pharmacaps, Inc. and have been
involved in the development of Valproic Acid DR
Capsules. Paula G. Davis, PhD, assisted with manu-
script preparation. In support of this, she received
financial assistance from JDS Pharmaceuticals,
New York, NY, USA and Noven Pharmaceuticals,
Miami, FL, USA. Jack Hoblitzell, PhD is acknowl-
edged for his contribution to the manuscript during his
tenure with Banner Pharmacaps, Inc.
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Paper CMRO-4449_5, Accepted for publication: 11 April 2008
Published Online: 27 May 2008
doi:10.1185/03007990802122735
1876 Valproic acid soft gelatin delayed-release capsule � 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(07)
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