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
Depakene Pharmacology, Pharmacokinetics, Studies, Metabolism - Valproic Acid
Depakene Pharmacology, Pharmacokinetics, Studies, Metabolism - Valproic Acid
CLINICAL PHARMACOLOGY
Pharmacodynamics
Valproic acid dissociates to the valproate ion in the gastrointestinal tract.
The mechanisms by which valproate exerts its antiepileptic effects have not
been established. It has been suggested that its activity in epilepsy is related
to increased brain concentrations of gamma-aminobutyric acid (GABA).
Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of DEPAKOTE (divalproex sodium) products and DEPAKENE
(valproic acid) capsules deliver equivalent quantities of valproate ion systemically.
Although the rate of valproate ion absorption may vary with the formulation
administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting
or postprandial) and the method of administration (e.g., whether the contents
of the capsule are sprinkled on food or the capsule is taken intact), these
differences should be of minor clinical importance under the steady state conditions
achieved in chronic use in the treatment of epilepsy.
However, it is possible that differences among the various valproate products
in T max and C max could be important upon initiation
of treatment. For example, in single dose studies, the effect of feeding had
a greater influence on the rate of absorption of the DEPAKOTE tablet (increase
in T max from 4 to 8 hours) than on the absorption of the DEPAKOTE
sprinkle capsules (increase in T max from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate
plasma concentrations vary with dosing regimen and formulation, the efficacy
of valproate as an anticonvulsant in chronic use is unlikely to be affected.
Experience employing dosing regimens from once-a-day to four-times-a-day, as
well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is
the primary determinant of seizure control and that differences in the ratios
of plasma peak to trough concentrations between valproate formulations are inconsequential
from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among
the various DEPAKOTE and DEPAKENE formulations should cause no clinical problems
in the management of patients with epilepsy (see DOSAGE AND ADMINISTRATION
). Nonetheless, any changes in dosage administration, or the addition or
discontinuance of concomitant drugs should ordinarily be accompanied by close
monitoring of clinical status and valproate plasma concentrations.
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 PRECAUTIONS
, 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 (beta)-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 m 2 and 11 L/1.73 m 2 , respectively. Mean plasma
clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m
2 and 92 L/1.73 m 2 . Mean terminal half-life for valproate
monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250
to 1000 mg.
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 glucuronosyltransferase
and other enzyme systems involved in valproate elimination) as well as increased
volume of distribution (in part 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., mL/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 m 2 ,
respectively).
Effect of Race:
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease:
Liver Disease (See BOXED WARNING , 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 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.
Clinical Trials
The studies described in the following section were conducted using DEPAKOTE
(divalproex sodium) tablets.
Epilepsy
The efficacy of DEPAKOTE 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 p ≤ 0.05 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,
carbamazepine, 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 |
Randomized 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 ≤
0.05 level. |
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