Ajman University of Science & Technology
Faculty of Pharmacy & Health Sciences
Clinical
Pharmacokinetics
Of Valproic Acid
Prepared by:
Dana Krayem 9860367
Supervised by:
Dr. Rafiq Abou Shaaban
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Contents

Chemical structure

Commonly used brand names

Mechanism of action

Pharmacokinetics (ADME)

Drug interactions:
A. Drugs that affect valproic acid
B. Effect of valproic acid on other drugs
3rd. An example to illustrate drug interaction of valproic acid

Time to sample

Adverse effects

Supplied

Questions & Answers
Valproic acid
Chemical Structure:
CH3
CH2
CH2
CH
CH3
CH2
COOH
CH2
Commonly used brand names are:




Depakene
Depacon
Depakote
Depakote Sprinkle
Mechanism of Action:
Valproic acid is a branched-chain fatty acid. Its chemical structure
differs significantly from any other anticonvulsant in current use. As with
other anticonvulsants, the mechanism of action of valproic acid is not
fully understood. It has been theorized that valproic acid acts by
increasing the concentrations of the inhibitory neurotransmitter gammaaminobutyric acid (GABA) within the central nervous system through
inhibition of GABA degradation or enhancement of GABA synthesis and
release. Other research has suggested that valproic acid acts via inhibition
of excitatory neurotransmitters or by action at sodium and calcium
channels to reduce sustained (high frequency repetitive) neuronal firing.
Pharmacokinetics:
Absorption
The time to reach maximum serum concentrations differs among
the products available. Peak concentrations occur approximately one to
three hours following administration of the capsule or liquid dosage
forms. Peak concentrations are delayed for up to three to five hours with
the sprinkle and delayed release tablet formulations. Administration of
valproic acid products with food delays the rate of absorption, but does
not typically affect the extent of drug absorbed. Also absorption is
delayed when drug is administered in the form of enteric-coated tablets.
Distribution
Valproic acid is rapidly distributed throughout the body and is
highly protein bound (~90%). The binding depends on the
concentration of binding proteins (i.e. albumin) and binding
modulators (e.g. free fatty acids). As a result, significant protein loss
may cause more free drug to be available, increasing clinical effect and
the potential for toxicity. Although not routinely used in patient
monitoring, free valproic acid serum concentrations can be measured
to assess changes in protein binding.
Metabolism
Valproic acid undergoes extensive hepatic metabolism. The
primary metabolic pathways include both glucuronidation and
oxidation, resulting in the formation of at least five different metabolic
products. The 2-en-valproic acid metabolite may be pharmacologically
active, while the 4-en-valproic acid may be involved in the
hepatotoxicity associated with this drug.
Elimination
Only 1 to 3% of a dose is excreted in the urine unchanged. The
usual elimination half-life of valproic acid in adults and children
greater than 10 years of age is 9 to 16 hours. Younger children have a
slightly shorter half-life of 7 to 13 hours, while infants have a
prolonged elimination (17 to 40 hours). The clearance of valproic acid
positively correlates with the unbound concentrations and is strongly
age-dependent, being low in neonates and high at the end of the first
postnatal month, and progressively decreasing from 2 months to 14
years.
Key Parameters
Therapeutic plasma
concentration
Bioavailability (F)
Salt form (S)
Volume of distribution (Vd)
50-100 mg/L
100 %
1
0.14 (0.1 – 0.5 ) L/kg
Clearance (Cl)
Children
Adults
13 mL/kg/hr
8 mL/kg/hr
Half-life (t 1/2)
Children
Adults
Children < 10 days
Cirrhoses or acute hepatitis
6 – 8 hr
10 – 12 hr
10 – 67 hr
up to 18 hr
Serum peak levels
Capsules & syrups
With food
Enteric–coated tablets (Divalproex Na)
1 – 4 hr
6 – 8 hr
3 – 4 hr
Drug interactions:
A – Drugs that affect valproic acid (VPA):
Drug
Effect
Phenobarbital
Inc. VPA clearance
Phenytoin
Inc. VPA clearance
Carbamazepine
Inc. VPA clearance
Primidone
Inc. VPA clearance
Rifampin
Inc. VPA oral clearance
Thorazine
Dec. VPA clearance
Cimetidine
Dec. VPA clearance
Zidovudine
Inc. AUC
Chlorpromazine
Inhibits VPA metabolism
Fluoxetine
Inhibits VPA metabolism
MAOIs
Inhibits VPA metabolism
Salicylates (eg.Aspirin)
Displaces VPA PPB
Charcoal
Dec. VPA absorption
B – Effect of valproic acid (VPA) on other
drugs:
Drug
Effect
Phenobarbital
Inhibits metabolism of phenobarbital
Carbamazepine
Inhibits metabolism of carbamazepine
Ethosuximide
Inhibits metabolism of ethosuximide
Felbamate
Inhibits metabolism of felbamate
Lamotrigine
Reduces metabolism of lamotrigine
Phenytoin
Displaces phenytoin PPB
Warfarin
Displaces warfarin PPB
Clozapine
Displaces clozapine PPB
Midazolam
Displaces midazolam PPB
Diazepam
Displaces diazepam PPB
Lorazepam
Reduces lorazepam plasma clearance
An example to illustrate drug interactions of valproic acid
is:
Effect of valproate on the pharmacokinetics and
pharmacodynamics of lorazepam: The pharmacokinetic-pharmacodynamic
interaction between valproate and lorazepam was evaluated in this randomized,
double-blind, placebo-controlled crossover study. Sixteen healthy male volunteers
enrolled in the study to receive either divalproex sodium (500 mg every 12 hours) or
matching placebo for 12 days in the first period, and then to receive the other regimen
for an identical second 12-day period. In both periods, lorazepam (1 mg every 12
hours) was administered on days 6 through 9 and on the morning of day 10.
Concomitant administration of divalproex sodium with lorazepam resulted in an 8%,
20%, and 31% increase in steady-state maximum plasma concentration, area under
the concentration-time curve, and trough plasma concentrations of lorazepam,
respectively. The apparent clearance of lorazepam through the formation of
lorazepam glucuronide was reduced by 31% during coadministration of divalproex
sodium. Pharmacokinetic properties of valproate did not change significantly in the
ten available participants during coadministration of lorazepam. Sedation scales
revealed no statistically significant differences in sedation between the two regimens.
It is concluded that valproate increases plasma concentrations and reduces clearance
of lorazepam, most likely by impairing hepatic glucuronidation, and that
coadministration of lorazepam does not affect the steady-state pharmacokinetic
properties of valproate.
Time to Sample :
Due to wide fluctuations in plasma valproate concentration within a dosing
interval, monitoring both the peak and trough concentrations of this drug would seem
to be desirable. Nevertheless, only trough concentrations are routinely monitored
because of the uncertainly about the time at which peak plasma concentrations will
occur and the difficulty evaluating markedly elevated valproic acid concentrations
given its capacity-limited plasma protein binding. In general, valproic acid
concentrations in plasma are monitored within two to four days following: 1)
initiation of therapy; 2) change in a dosing regimen; or 3) addition of other
antiepileptic drugs to the patient’s regimen. Valproic acid concentrations are also
measured whenever the patient’s clinical course has changed (e.g.,a decrease in
seizure control or laboratory or physical findings consistent with valproic acid
toxicity). As stated previously, there is some evidence that even though valproic acid
concentrations may have plateaued relatively rapidly, increased therapeutic effects
may continue to be observed for some time following the achievement of steady-state
valproic acid concentrations.
Adverse Effects
Gastrointestinal:
Nausea, vomiting and indigestion are the most commonly reported
side effects at the initiation of therapy. These effects are usually
transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps and constipation have also been reported. Anorexia
with some weight loss and increased appetite with some weight gain
have also been observed.
CNS Effects:
Sedative effects, ataxia, headache, nystagmus, diplopia, asterixis,
"spots before the eyes", tremor, dysarthria, dizziness and
incoordination. Rare cases of coma have been reported in patients
receiving valproic acid alone or in conjunction with phenobarbital.
Dermatologic:
Transient increases in hair loss , skin rash and petechiae have been
noted.
Endocrine:
Irregular menses and secondary amenorrhea in patients receiving
valproic acid. Abnormal thyroid function tests have been reported
Psychiatric:
Emotional upset, depression, psychosis, aggression, hyperactivity
and behavioural deterioration .
Musculoskeletal:
Weakness
Hematopoietic:
Thrombocytopenia has been reported. Valproic acid inhibits the
second phase of platelet aggregation. This may be reflected in altered
bleeding time. Bruising, hematoma formation and frank hemorrhage
have been reported. Relative lymphocytosis and hypofibrinogenemia
have been noted. Leukopenia and eosinophilia have also been reported.
Anemia and bone marrow suppression have been reported.
Hepatic:
Minor elevations of transaminases and LDH, increases in serum
bilirubin and abnormal changes in other liver function tests. These
results may reflect potentially serious hepatotoxicity
Metabolic:
Hyperammonemia & hyperglycinemia
Pancreatic:
Acute pancreatitis
Others:
Edema of the extremities
Supplied
Capsules:
250mg:
Each orange-colored, soft gelatin capsule contains: Valproic acid 250 mg. Also
contains methyl- and propylparaben. Alcohol-free, gluten-free, lactose-free, sucrosefree, sulfite-free and tartrazine-free. Bottles of 100 and 500.
500mg:
Each pale yellow, oval, soft gelatin enteric coated capsule contains: Valproic acid 500
mg. Also contains methyl- and propylparaben and tartrazine. Alcohol-free, glutenfree, lactose-free, sucrose-free and sulfite-free. Bottles of 100 and 500.
Syrup:
Each 5 mL of red syrup contains: The equivalent of 250 mg valproic acid, as the
sodium salt. Also contains methyl- and propylparaben and sucrose. Energy: 74.08 kJ
(17.70 kcal)/5 mL. Alcohol-free, gluten-free, lactose-free, sulfite-free and tartrazinefree. Bottles of 450 mL.
Questions & Answers
Question # 1
An eight-year-old, 25kg male, is receiving 250 mg of valproic acid Q 12
hr for absence seizures. While the seizure frequency has declined with
this therapy, he is still experiencing one to two absence seizures per day.
He has experienced no obvious side effects from the valproic acid therapy
and has normal renal and hepatic function. What is the expected trough
concentration for him on his current regimen?
Answer:
Cl = (13 mL/kg/hr) (25kg)
=325 mL/hr or 0.325 L/hr
Vd = (0.14 L) (25 kg)
= 3.5 L
Cl
Kd =
Vd
0.325 L/hr
=
3.5 L
= 0.093 hr-1
(S) (F) (Dose)
Cpssmin =
(e-Kdt)
Vd (1 – e-Kdt)
(1) (1) (250)
(e-(0.093) (12) )
=
(3.5) (1 – e-(0.093) (12))
= 34.8 mg/L ~ 35 mg/L
Question # 2
He had a measured trough concentration of 25 mg/L. Because of the
inadequate seizure control and the lack of apparent side effects, it is
decided to increase the trough concentration to 50 mg/L. What dose will
be required to achieve the target trough concentration of 50 mg/L if the
dosing interval is decreased from Q 12 hr to Q 8 hr?
Answer:
(S) (F) (Dose)
Cpssmax = [ Cpss min ]
+
Vd
(1) (1) (250)
= [25 mg/L] +
3.5 L
= 96.4 mg/L
ln (Cp1/Cp2)
Kd =
t
ln (96/25)
=
12
= 0.112 hr-1
(S) (F) (Dose)
Cpssmin
(e-Kdt)
=
Vd (1 –
e-Kdt)
( Cpssmin ) (Vd) (1 – e-Kdt)
Dose =
(S) (F) (e-Kdt)
(50) (3.5) (1 – e-(0.112) (8))
=
(1) (1) (e-(0.112) (8))
= 253 or ~ 250 mg
Question # 3
A 10-year-old, 32 kg female, is receiving valproic acid sprinkles
250 mg (2 * 125 mg) PO Q 8 hr for her seizure disorder. Calculate
her valproic acid level at steady state.
Answer:
(S) (F) (Dose / t)
Cpss
=
Cl
Cl = (13 mL/kg/hr) (32 kg)
= 416 mL/hr or 0.416 L/hr
(S) (F) (Dose / t)
Cpss
=
Cl
(1) (1) (250 mg/8 hr)
=
0.416 L/hr
= 75.1 mg/L
Question # 4
A 23-year-old, 70 kg female, is receiving phenobarbital 60 mg BID and
phenytoin 300 mg QD. The steady-state plasma drug concentrations are
18 mg/L for phenobarbital and 10 mg/L for phenytoin. Because of poor
seizure control, valproic acid 500 mg Q 8 hr was added to this drug
treatment regimen. Two months later, she complained of increased
drowsiness. At that time, plasma drug concentrations were measured and
reported as follows: phenobarbital 30 mg/L; phenytion 6 mg/L; and
valproic acid 75 mg/L. How can the increased phenobarbital
concentration and decreased phenytoin concentration be explained?
Answer:
Valproic acid decreases the clearance of phenobaraital by about
40%. The increase in plasma phenobarbital concentration from 18
mg/L to 30 mg/L 60 days after valproic acid was added is
consistent with a 40% decrease in phenobarbital clearance. If the
original steady-state phenobarbital concentration of 18 mg/L is
desired, the daily phenobarbital dose should be decreased by
about 40%.
The decline in plasma phenytoin concentration from 10 mg/L to 6
g/L is probably the result of competition for plasma protein binding
between valproic acid & phenytoin. In patients with normal serum
albumin concentrations & normal renal function, valproic acid (at a
concentration of ~ 70 mg/L) produces a 30% - 40% decline in
phenytoin plasma concentrations. This acute decline in the plasma
concentration of phenytoin is due to a decrease in the bound
concentration. The unbound or therapeutically active plasma
phenytoin concentration appears to remain unchanged because
any bound phenytoin which is displaced re-equilibrates with the
large tissue compartment. Since the tissue space is large, the
increased tissue concentrations will be negligible.
There is less well-documented evidence that chronic valproic acid
therapy increases the unbound phenytoin concentrations; this may
be caused by inhibition of phenytoin metabolism. To minimize the
impact competitive plasma protein binding on the assessment of
drug concentrations, both phenytoin & valproic acid samples
should be obtained when valproic acid concentrations are at their
lowest (that is, at trough, or just before the next dose).
Question # 5
"Jane" is an 18-year-old woman with a history of generalized tonic-clonic
seizures and myoclonic jerks. Her seizures were poorly controlled with
carbamazepine and phenytoin, but she has been seizure-free for 2 years
since starting valproic acid. However, over the past year she has gained
20 pounds. Upon review of systems, she also reports irregular menses for
the past 6 months. Explain.
Answer:
Weight gain is a particularly common side effect of valproic acid.
One study found that 57% of adult patients gained more than 4 kg
during valproic acid therapy. Another study found that 50% of adult
patients gained an average of 7 kg without any change in diet or
exercise. In a retrospective study of 100 children treated with
valproic acid, 44 had significant weight gain. This side effect does
not appear to be dose-related, but it can be minimized by diet and
exercise.
Serum sex hormones and vaginal ultrasonography were studied in
98 women with epilepsy and found menstrual disturbances in 10
(43%) of the 23 women being treated with valproate alone. Six
women had polycystic ovaries, and three had elevated serum
testosterone.
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