TDM of Valproic Acid

Juntip Kanjanasilp
Faculty of Pharmacy
Mahasarakham University
9 August 2009
Calculate the dose and concentration
Adjust dose and dosage regimens
Identify, resolve and prevent DRPs
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2
CHCOOH
Valproic acid pKa 4.7
Valproic acid
Various seizure disorders (absence and GTC)
Mechanisms:
voltage gated Na
+
channel Ca
2+
channel (T-
type)
GABA neurotransmitter
enzyme glutamic acid decarboxylase
GABA
enzyme GABA GABA-transaminase
succinic semialdehyde dehydrogenase

Valproic acid
Initial dose: 15 mg/kg/d
Highly bound to serum albumin
Enzyme inhibitors

Therapeutic Ranges
TR: 50-100 mg/L
Partial seizure: > 100 mg/L (55-100 mg/L)
GTC: > 50 mg/L
Generalized seizue: 30-65 mg/L
ADR:
N,V,D, abdominal cramps (6-45%)
Wt. gain (8-9%)
Alopecia, tremor, thrombocytopenia,
hepatotoxicity

Concentration dependent
Liver function test (11%)
CNS depression (ataxia, depression,
lethargy, tiredness)
Adrenergic tremor (> 100 mg/L)
Thrombocutopenia (6-40%)
Stupor, coma (> 175 mg/L)
Idiosyncratic ADRs
Fatal hepatotoxicity
Pancreatitis
Teratogenicity (1-2%) spina bifida
Folic acid 5 mg/d
Bioavailability
Rapidly and completely absorbed
Oral (fasting) --> Peak: 1-3 hours
Meal (food) --> peak late 6-8 hours
Enteric coated absorbed delayed 3-5 hrs
(lag time 2-4 hrs)

TIME TO SAMPLE
Dosage Form
Valproic acid (sugar coated tablet) 200 mg
Depakine

Chrono 500 mg
soft gelatin capsules 250 mg
Oral solution 200 mg/mL
syrup 250 mg/5 mL
divalproex sodium (Depakote)
enteric coated tablets 200 mg (125 mg,
250 mg, 500 mg)
Injection vial 400 mg/4 mL
Volume of Distribution (Vd)
0.1-0.5 L/kg
Low serum albumin/ end stage renal disease
variable Vd
Saturated binding serum albumin: valproic
acid > 50 mg/L (80-85 mg/mL)
Valproic acid 25-50 mg/L: Vd 0.14 L/kg
(assume normal albumin conc. and normal
renal function)
Clearance (Cl)
Almost entirely : hepatic metabolism
<5% renal (1-3%)
Dialysis : few
Cl: 6-10 mL/kg/hr (average 8 mL/kg/hr)
Pediatric and other antiepileptic drugs: Cl 10-13
mL/kg/hr
Trough conc. < 50 mg/L
Conc. proportional to the dose
One compartment linear model
Half-Life (t
1/2
)
4-17 hours (average 6-8 hours)
Children and other antiepileptic drugs:
reduced
Short half-life LD are not given
Dosing interval 8-12 hours fluctuation in
plasma concentration sustained released
Loading dose
Children:
Adult:
LD = (0.2 L/kg) X C (mg/L) X BW (kg)
LD = (0.15 L/kg) X C (mg/L) X BW (kg)
Key Parameters
TR 50-100 mg/L
F 1.0
S 1.0
Vd 0.14 (0.1-0.5) L/kg
Cl
Children
Adults

13 mL/kg/hr
8 mL/kg/hr
t1/2
Children
Adults

6-8 hr
10-12 hr
Time to sample
Monitor peak and trough
Uncertain time of peak Only trough
2-4 days following:
Initiation of therapy
Change dosage regimen
Addition of other antiepileptic drugs
Measured Decrease in seizure control or
toxicity
Diurnal variation

Special Population
Elderly:
Decrease protein binding increase unbound
Head trauma
Decrease protein binding
Pregnancy:
Increase clearance (3
rd
trimester) + Vd Total
plasma concentration decrease
Drug Interaction
Lamotrigine decrease dose of lamotrigine
50%
Meropenem decrease valproic acid level
May be increase renal excretion
Displace albumin binding
Case I
Children 8 y/o, 25 kg male
Absence seizures
Valproic acid 250 mg q 12 hr
1-2 absence seizures/d
No SE.
Normal renal and hepatic function
What is the expected trough
concentration?
Case I
Ave Cl for children: 13 mL/kg/hr
Ave Vd 0.14 L/kg
Cl = (13 mL/kg/hr)(25 kg)
= 325 mL/hr or 0.325 L/hr
Vd = (0.14 L/kg)(25 kg) = 3.5 L
Elimination rate constant(K) = Cl/Vd
= 0.093 hr
-1
T
1/2
= 0.693/K
= 7.5 hr
Case I
Assume steady state
Salt form(S) and bioavalability(F)= 1.0

Cpss min =
(S)(F)(Dose)/Vd
(1-e
-K
)
(e
-K
)

Cpss min = 34.8 mg/L 35 mg/L

Children 8 y/o, 25 kg male
Absence seizures
Valproic acid 250 mg q 12 hr
Measured trough conc. 25 mg/L
1-2 absence seizures/d
No SE.
Normal renal and hepatic function
Decided to increase the trough conc. 50 mg/L
What dose will be required to
achieve the target trough conc of
50 mg/L if the dosing interval is
decreased from q 12 hr 8 hr?
Cpss max = Cpss min + [(S)(F)(Dose)/Vd]
96.4 mg/L
K = [ln (Cp
1
/Cp
2
)]/t
K = 0.112 hr
-1
T
1/2
= 0.693/K = 6.2 hr
Cl = K*Vd = 0.392 L/hr
Cpss min =
(S)(F)(Dose)/Vd
(1-e
-K
)
(e
-K
)

Dose = 253 mg 250 mg

Female 23 y/o, 70 kg
Phenobarbital 60 mg bid 18 mg/L (Css)
Phenytoin 300 mg qd 10 mg/L (Css)
Poor seizure control
Add valproic acid 500
mg q 8 hr
2 mo later
Complained increased drowsiness
Phenobarbital 30 mg/L
Phenytoin 6 mg/L
Valproic acid 75 mg/L
How can the increased
phenobarbital concentration be
explained?
Valproic acid decreases the clearance of
phenobarbital by about 40% decreased
dose phenobarbital 40%?

How can the decreased
phenytoin concentration
be explained?
Competition for plasma protein binding
between valproic acid and phenytoin
Normal serum albumin and renal
function valproic acid conc 70 mg/L
30%-40% decline phenytoin concentration
Acute decline: decrease in the bound
concentration; unbound unchange
Chronic use: increase unbound phenytoin conc.
because inhibition of phenytoin metabolism



Both phenytoin and valproic acid samples
should be obtained when valproic acid
concentration are at trough

Female 10 y/o, 32 kg
Valproic acid 750 mg chrono qd
Calculate valproic acid level at steady state?

Not expect a great deal of fluctuation with
in the dosing interval

Cpss ave = (S)(F)(Dose/)/Cl
Cl = (13 mL/kg/hr)(32 kg)
= 416 mL/hr
= 0.416 L/hr
Cpss ave = (1)(1)(750 mg/ 24 hr)/ 0.416 L/hr
= 75.1 mg/L