Valproic acid

introduction
• Valproic acid is an agent that is chemically related to free fatty
acids and is used in the
treatment of generalized, partial, and absence (petit mal)
seizures
• Valproic acid is an agent that is chemically related to free fatty
acids and is used in the
treatment of generalized, partial, and absence (petit mal)
seizures
 THERAPEUTIC AND TOXIC CONCENTRATIONS

• The generally accepted therapeutic range for total valproic acid steady-
state concentrations is 50–100 μg/mL
• some clinicians suggest drug concentrations as high as
175 μg/mL with appropriate monitoring of serum concentrations and
possible adverse effects
• when the dose is increased total drug steady-state concentration increases
less than expected, but unbound steady-state drug concentration
increases in a proportional fashion
• identifies the clinical situations where unbound valproic acid serum
concentration measurement is useful
• measurement of unbound valproic acid serum concentrations should be
considered in
patients with factors known to alter valproic acid plasma protein binding
• In the upper end of the therapeutic range (>75 μg/mL) some patients will
begin to
experience the concentration-dependent adverse effects of valproic acid
therapy
 CLINICAL MONITORING PARAMETERS

• The goal of therapy with anticonvulsants is 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 (ataxia, sedation,
lethargy, tiredness, tremor, stupor, coma,
thrombocytopenia) as well as gastrointestinal
upset associated with local irritation of gastric mucosa
(nausea, vomiting, anorexia)
• Valproic acid serum concentrations should be measured in
most patients
 BASIC CLINICAL PHARMACOKINETIC PARAMETER

• Valproic acid is primarily eliminated by hepatic

metabolism (>95%)
• Hepatic metabolism
is via glucuronidation, β-oxidation, and α-
hydroxylation
• Valproic acid follows nonlinear
pharmacokinetics
owing to saturable, or concentration-
dependent, plasma protein binding
 EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

• For valproic acid, oral clearance (Cl/F) is 7–12 mL/h/kg and half-
life is 12–18 hours
for adults.
• n children 6–12 years old, oral clearance and half-life equal 10–20
mL/h/kg
and 6–8 hours, respectively
• Clearance rates can be higher and half-lives shorter in
patients receiving other hepatic drug–metabolizing enzyme
inducers
• Patients with liver cirrhosis or acute hepatitis have reduced
valproic acid clearance because
of destruction of liver parenchyma
 DRUG INTERACTIONS

• Other antiepileptic drugs that have their clearance rates decreased and
steady-state concentrations increased by valproic acid-related enzyme inhibition include
clonazepam, carbamazepine, phenytoin, primidone, lamotrigine, and ethosuximide
• Valproic acid therapy also decreases the clearance and increases steady-state
concentrations
of other drugs including zidovudine, amitriptyline, and nortriptyline

• other drugs can affect valproic acid clearance and steady-state serum
concentrations.28 Phenytoin, lamotrigine, rifampin, and carbamazepine can increase
valproic acid clearance and decrease valproic acid steady-state serum concentrations
• Cimetidine, chlorpromazine, and felbamate are examples of drugs that decrease
valproic acid
clearance and increase valproic acid steady-state concentrations.
• Because valproic acid is highly protein bound, plasma protein binding drug interactions
can occur with other drugs that are highly bound to albumin.
 INITIAL DOSAGE DETERMINATION
METHODS
1. Pharmacokinetic Dosing Method
• CLEARANCE ESTIMATE
Valproic acid is predominately metabolized by liver. Unfortunately,
there is no good
way to estimate the elimination characteristics of liver metabolized
drugs using an
endogenous marker of liver function
• Because of this, a patient is categorized according to the disease
states and
conditions that are known to change valproic acid clearance, and the
clearance previously
measured in these studies is used as an estimate of the current
patient’s clearance
• VOLUME OF DISTRIBUTION ESTIMATE

Valproic acid volume of distribution is assumed to

equal 0.15 L/kg for adults and
0.2 L/kg for children under 12 years of age. Thus, for
an 80-kg adult patient, the estimated valproic
volume of distribution would be 12 L: V = 0.15 L/kg
⋅ 80 kg = 12 L
• HALF-LIFE AND ELIMINATION RATE CONSTANT
ESTIMATE
valproic acid half-life (t1/2) and elimination rate
constant (k) estimates using the following
equations:
t1/2 = (0.693 ⋅ V) / Cl, k = 0.693/t1/2 = Cl/V.
• SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL
AND EQUATIONS
When oral therapy is required, valproic acid has
good bioavailability (F = 1), and every 8–12 hour dosing
provides a relatively smooth
serum concentration/time curve that emulates an
intravenous infusion

maintenancedosage calculation:
Css = [F(D/τ)] / Cl or D = (Css ⋅ Cl ⋅ τ) / F
2. Literature-Based Recommended Dosing
• Usual initial maintenance doses for pediatric patients are
10 mg/kg/d if the child is not taking
a hepatic enzyme inducer (phenytoin, phenobarbital,
carbamazepine, and rifampin) or
20 mg/kg/d if the child is taking a hepatic enzyme inducer.
• For adults, initial maintenance
doses are 7.5 mg/kg/d if the patient is not taking hepatic
enzyme inducers or 15 mg/kg/d if a
hepatic enzyme inducer is concurrently administered
• Several methods to initiate valproic acid
therapy are available. The pharmacokinetic
dosing method is the most flexible of the
techniques.
 USE OF VALPROIC ACID SERUM CONCENTRATIONS
TO ALTER DOSES

1. Pseudolinear Pharmacokinetics Method

to approximate new total serum concentrations after a
dosage adjustment with valproic acid is to
temporarily assume linear pharmacokinetics, then
subtract 10–20% for a dosage increase or add 10–
20% for a dosage decrease to account for nonlinear,
concentration-dependent plasma protein binding
pharmacokinetics:

Dnew = (Cssnew/Cssold)Dold
2. Pharmacokinetic Parameter Method
• valproic acid clearance (Cl): Cl = (D/τ) / Css
• If the patient is receiving oral valproic acid
therapy, valproic
acid clearance (Cl) can be calculated using the
following formula: Cl = [F(D/τ)] / Css
• volume of distribution (V) is
calculated using the following equation: V = D/(C
postdose − Cpredose)