VALPROIC ACID

Valproic Acid
Valproic Acid is agent that is chemically related to free fatty acids and is used
in the treatment of generalized, partial, and absence (petit mal) seizures.

It has thewidest spectrum of activity compared to the other currently

available antiepileptic drugs.

Now available in intravenous, as well as oral, form, valproic acid can be used
for the acute treatment and chronic prophylaxis of seizures.

Also a useful agent for the treatment of bipolar affective disorders and the
prevention of migraine headaches.

Its antiepileptic effect is thought to result from

its ability to increase concentrations of the neuroinhibitor -aminobutyric acid (GABA),

to potentiate the postsynaptic response to GABA,

to exert a direct effect on cellular membranes.

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 THERAPEUTIC AND TOXIC
CONCENTRATIONS
The generally accepted therapeutic range for total valproic
acid Css : 50100 g/mL.
some clinicians suggest drug concentrations as high as 175
g/mL with appropriate monitoring of serum concentrations
and possible adverse effects.
highly protein bound to albumin with typical values of 90
95%.
Plasma protein binding of valproic acid is saturable within the
therapeutic range, which results in less protein binding and
higher unbound fraction of drug at higher concentrations.

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 The concentration-dependent protein
binding of valproic acid causes the drug to
follow nonlinear pharmacokinetics
(fundamentally different from phenytoin)
In the case of valproic acid, when the dose
total drug steady-state concentration
less than expected, but unbound steady-
state drug concentration in a
proportional fashion.
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 unbound steady-state concentration therapeutic range for
valproic acid of 2.510.
As is the case with phenytoin, measurement of unbound
valproic acid serum concentrations should be considered in
patients with factors known to alter valproic acid plasma
protein binding.
These factors fall into three broad categories :
lack of binding protein where there are insufficient plasma
concentrations of albumin
displacement of valproic acid from albumin binding sites by
endogenous compounds
displacement of valproic acid from albumin binding sites by
exogenous compounds
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Disease States and Conditions
that Alter Valproic Acid Plasma
Protein Binding

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 In the upper end of the therapeutic range (>75
g/mL) some patients will begin to experience the
concentration-dependent adverse effects of
valproic acid therapy : ataxia, sedation, lethargy,
and tiredness.
Other concentration-related side effects of
valproic acid therapy include:
tremor : concentrations >100 g/mL

stupor or coma : concentrations >175 g/mL

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 CLINICAL MONITORING
PARAMETERS
The goal of therapy with anticonvulsants to reduce seizure
frequency and maximize quality of life with a minimum of
adverse drug effects.

Patients should be monitored for concentration-related side

effects (local irritation of gastric mucosa)

Valproic acid serum concentrations should be measured in most

patients.

Valproic acid serum concentrations are also valuable tools to

avoid adverse drug effects. Patients are more likely to accept
drug therapy if adverse reactions are held to the absolute
minimum.
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 BASIC CLINICAL
PHARMACOKINETIC
PARAMETERS
Valproic acid is primarily eliminated by hepatic metabolism
(>95%).

Hepatic metabolism is via glucuronidation, -oxidation, and -

hydroxylation.

Over 10 metabolites have been identified for valproic acid, and

the 4-en-valproic acid metabolite may be associated with the
drugs propensity to cause hepatotoxicity.

About 15% of a valproic acid dose is recovered in the urine as

unchanged drug.

Valproic acid is eliminated almost completely by hepatic

metabolism, and it is a low hepatic extraction ratio drug.
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 This is the reason total steady-state concentrations
increase disproportionately after a valproic acid dosage
increase.

F : valproic acid bioavailability

D : valproic acid dose

: the dosage interval

ClH : hepatic clearance

However, since unbound steady-state concentrations

are only influenced by intrinsic clearance, unbound
concentrations increase in a proportional amount to
dose
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 Valproic acid volume of distribution (V = 0.15 0.2
L/kg) is also affected by
concentration-dependent plasma protein binding
and is determined by the physiologic volume of
blood (VB) and tissues (VT)
the unbound fraction of drug in the blood (fB) and
tissues (fT)

As valproic acid concentrations, unbound fraction of

drug in the bloodwhich causes an in the volume of
distribution for the drug

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 t1/2 is related to clearance and volume of distribution using
the same equation as for linear pharmacokinetics

On average, valproic acid half-life is 1218 hours in adult

patients with total concentrations within the therapeutic
range.
Valproic acid is available as three different entities (all of
them are prescribed as valproic acid equivalents)
valproic acid

sodium valproate (the sodium salt of valproic acid)

divalproex sodium (a stable coordination compound

consisting of a 1:1 ratio of valproic acid and sodium
valproate)
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 EFFECTS OF DISEASE STATES AND
CONDITIONS
ForON PHARMACOKINETICS
valproic acid, oral clearance : AND DOSING
(Cl/F) is 712 mL/h/kg and half-life is 1218 hours for adults

In children 612 years old, oral clearance and half-life equal 1020
mL/h/kg and 68 hours
Clearance rates can be higher and half-lives shorter in patients
receiving other hepatic drugmetabolizing enzyme inducers
For adults receiving other antiepileptic drugs that are enzyme
inducers, valproic acid clearance
adults is 1518 mL/h/kg and half-lives range from 4 to 12 hours

Children is 2030 mL/h/kg and half-life is 46 h

Valproic acid volume of distribution (V/F) is 0.150.2 L/kg

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 DRUG INTERACTIONS
Valproic acid is a potent inhibitor of hepatic drug metabolizing
enzyme systems and glucuronidation
antiepileptic drugs that have their clearance rates and Css
by valproic acid-related enzyme inhibition (clonazepam,
carbamazepine, phenytoin, primidone, lamotrigine, and
ethosuximide)
Valproic acid therapy also the clearance and Css of other
drugs (zidovudine, amitriptyline, and nortriptyline)
Phenytoin, lamotrigine, rifampin, and carbamazepine can
valproic acid clr and valproic acid steady-state serum
concentrations
Cimetidine, chlorpromazine, and felbamate are examples of
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drugs that valproic acid clearance and valproic acid steady-
 Aspirin, warfarin, and phenytoin all have
plasma protein binding drug interactions
with valproic acid, and these drugs have
higher unbound fractions when given
concurrently with valproic acid.
The drug interaction between valproic acid
and phenytoin deserves special examination
because of its complexity and because these
two agents are regularly used together for
the treatment of seizures
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 INITIAL DOSAGE
DETERMINATION

METHODS
Pharmacokinetic dosing method
CLEARANCE ESTIMATE
VOLUME OF DISTRIBUTION ESTIMATE
HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE
SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND
EQUATIONS
Literature-Based Recommended Dosing

USE OF VALPROIC ACID SERUM CONCENTRATIONS TO ALTER DOSES

Pseudolinear Pharmacokinetics Method

Pharmacokinetic Parameter Method
BAYESIAN PHARMACOKINETIC COMPUTER PROGRAMS

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