Antiepileptic drugs

1. CLINICAL CHEMISTRY 2
Gail Ann P. Pascual, RMT, MPH
1 Clinical Chemistry 2 – Therapeutic Drug Monitoring | Angelica Mae L. Balino, fRMT 3D | 2023
ANTIEPILEPTIC DRUGS
DRUG USE
ROUTE OF
ADMINISTRATION
HALF-LIFE ELIMINATION
THERAPEUTIC
RANGE
SPECIMEN CONSIDERATION
Primidone
control of grand mal seizures
that are refractory (resistant) to
other antiepileptic drugs
oral administration
(peak: after 2 hours)
8 hours Hepatic metabolism
5.0 to 12.0 µg/mL
for adults.
When monitoring primidone and
phenobarbital levels simultaneously,
the specimen should be drawn just
before the next dose is administered.
Phenobarbital
(Luminal;
Solfoton)
slow-acting barbiturate that
effectively controls several
types of seizures
oral administration 70 to 100
hours
Hepatic metabolism
(renal filtration)
20.0 to 40.0 µg/mL
for adults
After initiation of therapy, dose
adjustment is usually required after
the induction period is complete. For
most individuals, this occurs within
10 to 15 days after the initial dose.
Phenytoin
(Dilantin)
• treatment of seizure
disorders;
• short-term prophylactic
agent in brain injury to
prevent loss of functional
tissue
oral administration
(peak: 3 to 12 hours
post dose)
GI absorption: variable
and sometimes
incomplete
6 to 24 hours Hepatic metabolism
• 10 to 20 μg/mL
• 1 to 2 μg/mL
(free phenytoin)
The therapeutic range must be
individualized to suit the clinical
situation.
Valproic acid
(Valproate;
Depakote)
treatment of petit mal and
absence seizures
oral preparation
GI absorption: rapid
and complete
11 to 17 hours Hepatic metabolism 50 to 120 μg/mL
• Determination of blood
concentrations is primarily
performed to ensure that toxic
levels (>120 μg/mL) are not
present.
• Hepatic markers should be
checked frequently during the first
6 months of therapy.
Carbamazepine
(Tegretol)
treatment for various seizure
disorders; used when patients
do not respond well to other
AEDs.
oral administration
(peak: 4 to 8 hours) 10 to 20 hours Hepatic metabolism 4 to 12 μg/mL
Carbamazepine is an inducer of
hepatic metabolism, so its blood
concentrations must be frequently
monitored. When indicated, dosage
adjustments are guided by
monitoring serum levels.

2. CLINICAL CHEMISTRY 2
Gail Ann P. Pascual, RMT, MPH
2 Clinical Chemistry 2 – Therapeutic Drug Monitoring | Angelica Mae L. Balino, fRMT 3D | 2023
Ethosuximide
(Zarontin)
controlling petit mal seizures
oral preparation
(peak: 2 to 4 hours)
40 to 60 hours
Hepatic metabolism;
Renal filtration (20%)
40 to 100 μg/mL
TDM for ethosuximide is performed
to ensure that blood concentrations
are in the therapeutic range
Felbamate
(Felbatol)
use in severe epilepsies such as
in children with the mixed
seizure disorder, Lennox-
Gastaut syndrome, and in adults
with refractory epilepsy
oral preparation
GI absorption: nearly
complete
(peak: 1 to 4 hours)
14 to 22 hours
in adults
Renal and Hepatic
metabolism
25 to 60 μg/mL
Hepatic metabolism is enhanced by
enzyme inducers such as
phenobarbital, primidone,
phenytoin, and carbamazepine and
results in a decreased half-life.
Gabapentin
(Neurontin)
monotherapy or in conjunction
with other AEDs for patients
suffering from complex partial
seizures with or without
generalized seizures and for
pain management in some
scenarios
oral administration
(peak: 2 to 3 hours)
5 to 9 hours in
patients with
normal renal
function
Renal infiltration 12 and 20 μg/mL
Children require a higher dose than
adults to maintain a comparable
half-life as they eliminate the drug
faster than adults.
Lamotrigine
(Lamictal)
treat patients with partial and
generalized seizures.
oral preparation
GI absorption: rapid
and complete
(peak: 3 hours)
15 to 30 hours Hepatic metabolism 2.5 to 15 μg/mL
The rate of elimination is highly
dependent on patient age and
physiologic condition. Younger
infants tend to metabolize this drug
slower than older infants, and
children metabolize lamotrigine
twice as quickly as adults.
Levetiracetam
(Keppra)
used in partial and generalized
seizures
oral administration
(peak: 1 hour)
6 to 8 hours
(increased in
children and
pregnant
females and
decreased in
the elderly)
Renal filtration 12.0 to 35.0 μg/mL
lack of pharmacokinetic variability
but may be useful in monitoring
adherence and fluctuating
concentrations during pregnancy
Oxcarbazepine
(Trileptal)
treatment of partial seizures
and secondarily in generalized
tonic–clonic seizures
oral administration
(peak: 8 hours)
8 to 10 hours
(adults)
Hepatic metabolism 12 to 35 μg/mL
Children have a higher clearance rate
need a higher dosing regimen to
obtain the optimal blood
concentration compared with adults.
In the elderly population, the drug

3. CLINICAL CHEMISTRY 2
Gail Ann P. Pascual, RMT, MPH
3 Clinical Chemistry 2 – Therapeutic Drug Monitoring | Angelica Mae L. Balino, fRMT 3D | 2023
clearance is reduced by 30%, so a
lower dosage regimen is needed to
maintain therapeutic concentrations.
Tiagabine
(Gabitril)
treatment of partial seizures
oral administration
GI absorption: rapid
and nearly complete
(peak: 1-2 hours)
4 to 13 hours. Hepatic metabolism 20 to 100 ng/mL
the ratio of free to bound drug is
affected by other protein-binding
drugs such as valproic acid,
naproxen, and salicylates and by
pregnancy. It is highly metabolized
by the hepatic MFO pathway, so
hepatic dysfunction can increase the
half-life of the drug.
Topiramate
(Topamax)
treatment of partial and
generalized seizures
oral administration
(peak: 1-4 hours)
20 to 30 hours
renal filtration;
(some: hepatic
metabolism)
<25 mg/L
The dose-to-blood concentration
ratio in children is less than that of
adults such that children require a
higher dose to maintain plasma
topiramate concentrations
compared to adults. 13 Blood
concentrations are increased
secondary to renal insufficiency but
may be decreased when used with
other enzyme-inducing AEDs.
Zonisamide
(Zonegram)
anticonvulsant used in
adjunctive therapy for partial
and generalized seizures
oral administration
GI absorption: 65% or
higher
(peak: 4-7 hours)
50 to 70 hours
(px w/
monotherapy);
25 to 35 hours
when other
enzyme-
inducing AEDs
are
administered
concomitantly.
Hepatic metabolism
(acetylation;
oxidation;
glucuronide
conjugation; renal
excretion)
10 to 40 μg/mL
Children require higher doses to
achieve therapeutic blood
concentrations compared to those of
adults.

4. CLINICAL CHEMISTRY 2
Gail Ann P. Pascual, RMT, MPH
4 Clinical Chemistry 2 – Therapeutic Drug Monitoring | Angelica Mae L. Balino, fRMT 3D | 2023
PSYCHOACTIVE DRUGS
DRUG USE
ROUTE OF
ADMINISTRATION
HALF-LIFE ELIMINATION
THERAPEUTIC
RANGE
SPECIMEN
CONSIDERATION/
COMMENTS
Lithium
mood-altering drug primarily used
in the treatment of bipolar disorder,
recurrent depression, and
aggressive or self-mutilating
behavior, though it may also be
used as a preventative treatment for
migraines and cluster headaches
oral administration
GI absorption:
rapid and complete
(peak: 2-4 hours)
10 to 35 hours renal filtration 0.5 to 1.2 mmol/L
Test tubes that contain lithium
anticoagulants must be avoided to
prevent falsely increased specimen
results.
Tricyclic
Antidepressants
to treat depression, insomnia,
extreme apathy, and loss of libido
oral administration
GI absorption:
variable
(peak: 2-12 hours)
17 to 40 hours
hepatic
metabolism
The rate of elimination can also be
influenced by coadministration of
other drugs that are eliminated by
hepatic metabolism.
Clozapine
treatment of otherwise treatment-
refractory schizophrenia
oral administration
GI absorption:
rapid and complete
(peak: 2 hours)
8 to 16 hours
hepatic
metabolism
350 to 420 ng/mL
TDM may be indicated to check for
adherence and in patients with
altered pharmacokinetics.
Olanzapine
thienobenzodiazepine derivative
that effectively treats schizophrenia,
acute manic episodes, and the
recurrence of bipolar disorders
oral administration
GI absorption: well
(peak: 5-8 hours)
fast-acting
intramuscular (IM)
injection
21 to 54 hours
hepatic
metabolism
20 to 50 ng/mL
Estimated 40% is inactivated by first-
pass metabolism.

5. CLINICAL CHEMISTRY 2
Gail Ann P. Pascual, RMT, MPH
5 Clinical Chemistry 2 – Therapeutic Drug Monitoring | Angelica Mae L. Balino, fRMT 3D | 2023
IMMUNOSUPPRESSIVE DRUGS
DRUG USE
ROUTE OF
ADMINISTRATION
HALF-LIFE ELIMINATION
THERAPEUTIC
RANGE
SPECIMEN CONSIDERATION
Cyclosporine
suppression of host-
versus-graft rejection of
heterotopic transplanted
organs
oral administration
GI absorption: 5-50%
(peak: 1-6 hours)
approximately
12 hours
hepatic metabolism 100 to 400 ng/mL
Erythrocyte content is highly temperature
dependent; therefore, evaluation of blood
cyclosporine concentrations requires
rigorous control of specimen
temperatures. Therefore, whole blood
specimens are used to avoid this
preanalytical variable.
Tacrolimus
immunosuppressive drug
that is 100 times more
potent than cyclosporine
oral administration
GI absorption: highly
variable
(peak: 1-3 hours)
10 to 12 hours hepatic metabolism 5–15 ng/mL
Tacrolimus has been associated with
thrombus formation at concentrations
above its therapeutic range.
Sirolimus
antifungal agent with
immunosuppressive
activity that is used to
prevent graft rejection in
patients receiving a kidney
transplant
oral administration
GI absorption: rapid
(peak: 1-2 hours)
62 hours hepatic metabolism
4 to 12 μg/L
(sirolimus +
cyclosporine)
12 to 20 μg/L
(sirolimus only)
To increase the therapeutic efficacy,
sirolimus is commonly co-administered
with cyclosporine or tacrolimus as the
bioavailability of sirolimus is 15% when
taken in conjunction with cyclosporine.
Everolimus
prophylaxis of graft
rejection in solid organ
transplant
shorter than
sirolimus
metabolized by
CYP3A4
3 and 8 ng/mL
Mycophenolic
Acid
lymphocyte proliferation
inhibitor that is used most
commonly as
supplemental therapy
with cyclosporine and
tacrolimus in renal
transplant patients.
oral administration
(peak: 1-2 hours)
17 hours
renal excretion
(>90%)
1 to 3.5 μg/mL
Mycophenolate mofetil is a prodrug that is
rapidly converted in the liver to its active
form, mycophenolic acid (MPA).
As with the other anti-rejection drugs, low
trough concentrations of MPA increase the
risk of acute rejection, while high
concentrations imply toxicity.

6. CLINICAL CHEMISTRY 2
Gail Ann P. Pascual, RMT, MPH
6 Clinical Chemistry 2 – Therapeutic Drug Monitoring | Angelica Mae L. Balino, fRMT 3D | 2023
ANTINEOPLASTICS
DRUG USE
ROUTE OF
ADMINISTRATION
HALF-LIFE ELIMINATION
THERAPEUTIC
RANGE
SPECIMEN
CONSIDERATION/
COMMENTS
Methotrexate
an effective therapy for
various neoplastic
conditions
oral administration
(peak: 1 hour)
5 to 9 hours Renal filtration < 1 μmol/L 48
Trough serum specimens
are preferred for
determination of
methotrexate
concentrations.
BRONCHODILATORS
Theophylline
(Theo-Dur, Theo-24,
Uniphyl)
treatment of respiratory
disorders, such as
asthma and stable
chronic obstructive
pulmonary disease, for
patients that have
difficulty using an inhaler
or those with nocturnal
symptoms
oral administration
(peak: 1 hour)
Absorption can be
variable, with peak blood
concentrations achieved
1 to 2 hours after dosing
when a rapid-release
formation is
administered or within 4
to 8 hours for a
modified-release
preparation
3 to 8 hours
hepatic metabolism;
renal filtration (20%)
10 to 20 µg/L
There is a poor
correlation between
dosage and blood
concentrations; however,
TDM may initially be
useful in optimizing the
dosage or the
confirmation of toxicity
when suspected.