A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Depacon Pharmacology, Pharmacokinetics, Studies, Metabolism - Valproate
Depacon Pharmacology, Pharmacokinetics, Studies, Metabolism - Valproate
CLINICAL PHARMACOLOGY
DEPACON exists as the valproate ion
in the blood. The mechanisms by which valproate exerts its therapeutic
effects have not been established. It has been suggested that its
activity in epilepsy
is related to increased brain
concentrations of gammaaminobutyric acid
(GABA).
Pharmacokinetics
Bioavailability
Equivalent doses of intravenous
(IV) valproate and oral
valproate products are expected to result in equivalent
C max, C min, and total systemic
exposure to the valproate
ion. However, the rate
of valproate ion absorption
may vary with the formulation used. These differences should be
of minor clinical
importance under the steady state
conditions achieved in chronic
use in the treatment
of epilepsy.
Administration of DEPAKOTE (divalproex sodium) tablets and IV
valproate (given as a one hour infusion), 250 mg
every 6 hours for 4 days to 18 healthy
male volunteers resulted
in equivalent A.C.
C max , C min at steady state, as well as
after the first dose. The T max after IV
DEPACON occurs at the end
of the one hour infusion,
while the T max after oral
dosing with DEPAKOTE occurs at approximately 4 hours. Because the
kinetics of unbound
valproate are linear, bioequivalence
between DEPACON and DEPAKOTE up to the maximum
recommended dose of 60
mg/kg/day can be assumed. The AUC
and Cmax resulting from administration
of IV valproate 500 mg
as a single one hour infusion
and a single 500 mg dose
of DEPAKENE syrup to 17
healthy male
volunteers were also equivalent.
Patients maintained on valproic acid
doses of 750 mg to 4250 mg
daily (given in divided doses every 6 hours) as oral
DEPAKOTE (divalproex sodium) alone (n= 24) or with another stabilized
antiepileptic
drug [carbamazepine (n=
15), phenytoin (n=
11), or phenobarbital
(n= 1)], showed comparable plasma
levels for valproic acid
when switching from oral
DEPAKOTE to IV valproate
(1-hour infusion).
Distribution
Protein Binding: The plasma
protein binding of valproate
is concentration
dependent and the free fraction
increases from approximately 10% at 40 µg/mL to 18.5% at 130
µg/mL. Protein binding of valproate is reduced in the elderly,
in patients with chronic
hepatic diseases, in
patients with renal impairment,
and in the presence of other drugs (e. g., aspirin). Conversely,
valproate may displace certain protein-bound drugs (e. g., phenytoin,
carbamazepine, warfarin, and tolbutamide). (See DRUG
INTERACTIONS for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution: Valproate concentrations in cerebrospinal
fluid (CSF) approximate
unbound concentrations in plasma
(about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In
adult patients on monotherapy,
30-50% of an administered dose
appears in urine as a
glucuronide conjugate.
Mitochondrial b -oxidation is the other major
metabolic pathway, typically accounting for over 40% of the dose.
Usually, less than 15-20% of the dose
is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted
unchanged in urine.
The relationship between dose
and total valproate concentration
is nonlinear; concentration
does not increase proportionally with the dose, but rather, increases
to a lesser extent due to saturable plasma
protein binding. The
kinetics of unbound
drug are linear.
Elimination
Mean plasma clearance
and volume of distribution
for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73
m2 , respectively. Mean terminal
half-life for valproate
monotherapy after
a 60 minute intravenous
infusion of 1000 mg
was 16 ± 3.0 hour
The estimates cited apply primarily to patients who are not taking
drugs that affect hepatic
metabolizing enzyme systems.
For example, patients taking enzyme-inducing antiepileptic
drugs (carbamazepine, phenytoin, and phenobarbital) will
clear valproate more rapidly. Because of these changes in valproate
clearance, monitoring
of antiepileptic
concentrations should be intensified whenever concomitant
antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age: Neonates - Children
within the first two months of life
have a markedly decreased ability
to eliminate valproate
compared to older children and adults. This is a result of reduced
clearance (perhaps
due to delay in development
of glucuronosyl transferase
and other enzyme systems
involved in valproate elimination) as well as increased volume
of distribution
(in proof due to decreased
plasma protein
binding). For example, in one study, the half-life
in children under 10 days ranged from 10 to 67 hours compared to
a range of 7 to 13 hours
in children greater than 2 months.
Children - Pediatric patients (i. e., between
3 months and 10 years) have 50% higher clearances expressed on weight
(i. e.,L/min/kg) than do adults. Over the age
of 10 years, children have pharmacokinetic parameters that approximate
those of adults.
Elderly -The capacity
of elderly patients (age range: 68 to 89 years) to eliminate
valproate has been shown to be reduced compared to younger adults
(age range: 22 to 26). Intrinsic clearance
is reduced by 39%; the free fraction
is increased by 44%. Accordingly, the initial
dosage should be reduced
in the elderly. (See DOSAGE AND
ADMINISTRATION ).
Effect of Gender: There are no
differences in the body
surface area
adjusted unbound clearance
between males and females (4.8 ± 0.17 and 4.7 ± 0.07
L/hr per 1.73 m2
, respectively).
Effect of Race: The effects of race
on the kinetics of
valproate have not been studied.
Effect of Disease: Liver Disease
-(See CONTRAINDICATIONS,
and WARNINGS ). Liver disease
impairs the capacity
to eliminate valproate.
In one study, the clearance
of free valproate was decreased by 50% in 7 patients with cirrhosis
and by 16% in 4 patients with acute
hepatitis, compared
with 6 healthy subjects.
In that study, the half-life
of valproate was increased from 12 to 18 hours. Liver disease
is also associated with decreased albumin
concentrations and larger unbound fractions (2 to 2.6 fold
increase) of valproate. Accordingly, monitoring of total concentrations
may be misleading since free concentrations may be substantially
elevated in patients with hepatic
disease whereas total
concentrations may appear to be normal.
Renal Disease -A slight reduction
(27%) in the unbound clearance
of valproate has been reported in patients with renal
failure (creatinine
clearance < 10
mL/minute); however, hemodialysis
typically reduces valproate concentrations by about 20%. Therefore,
no dosage
adjustment appears
to be necessary in patients with renal
failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
Plasma Levels and Clinical Effect
The relationship between plasma
concentration
and clinical response
is not well documented. One contributing factor
is the nonlinear, concentration
dependent protein binding
of valproate which affects the clearance
of the drug. Thus, monitoring of total serum
valproate cannot provide a reliable index
of the bioactive valproate
species.
For example, because the plasma
protein binding of valproate
is concentration
dependent, the free fraction
increases from approximately 10% at 40 µg/mL to 18.5% at 130
µg/mL. Higher than expected free fractions occur in the elderly,
in hyperlipidemic patients, and in patients with hepatic
and renal diseases.
Epilepsy
The therapeutic
range in epilepsy
is commonly considered to be 50 to 100 µg/mL of total valproate,
although some patients may be controlled with lower or higher plasma
concentrations.
Equivalent doses of DEPACON and DEPAKOTE (divalproex sodium) yield
equivalent plasma
levels of the valproate ion
(see Pharmacokinetics - above).
CLINICAL STUDIES
The studies described in the following section
were conducted with oral
divalproex sodium products.
Epilepsy
The efficacy of DEPAKOTE
(divalproex sodium) in reducing the incidence
of complex partial seizures
(CPS) that occur in isolation
or in association
with other seizure types
was established in two controlled trials.
In one, multiclinic, placebo
controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer
eight or more CPS per 8
weeks during an 8 week period
of monotherapy with
doses of either carbamazepine
or phenytoin sufficient
to assure plasma concentrations
within the "therapeutic range" were randomized to receive, in addition
to their original antiepilepsy drug
(AED), either DEPAKOTE or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following table
presents the findings.
Adjunctive Therapy Study
Median Incidence of CPS per
8 Weeks
|
Add-on Treatment
|
Number of Patients
|
Baseline Incidence
|
Experimental Incidence
|
|
DEPAKOTE
|
75
|
16.0
|
8.9*
|
|
Placebo
|
69
|
14.5
|
11.5
|
*Reduction from baseline
statistically significantly greater for DEPAKOTE than placebo
at p³0.05 level.
The second study assessed the capacity
of DEPAKOTE to reduce
the incidence of CPS
when administered as the sole
AED. The study compared the incidence
of CPS among patients randomized to either a high or low dose
treatment arm. Patients
qualified for entry into the randomized comparison phase
of this study only if 1) they continued to experience
2 or more CPS per 4 weeks
during an 8 to 12 week long period
of monotherapy with
adequate doses of an AED
(i. e., phenytoin, carba mazepine, phenobarbital, or primidone)
and 2) they made a successful transition
over a two week interval
to DEPAKOTE. Patients entering the randomized phase
were then brought to their assigned target
dose, gradually tapered off their concomitant
AED and followed for an
interval as long as
22 weeks. Less than 50% of the patients randomized, however, completed
the study. In patients converted
to DEPAKOTE monotherapy, the mean
total valproate concentrations during monotherapy
were 71 and 123 µg/mL in the low dose
and high dose groups, respectively.
The following table presents
the findings for all patients randomized who had at least one post-randomization
assessment.
Monotherapy Study
Median Incidence of CPS per
8 Weeks
|
Treatment
|
Number of Patients
|
Baseline Incidence
|
Randomize Phase Incidence
|
|
High dose DEPAKOTE
|
131
|
13.2
|
10.7*
|
|
Low dose DEPAKOTE
|
134
|
14.2
|
13.8
|
*Reduction from baseline
statistically significantly greater for high dose
than low dose at p ³
0.05 level.
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