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ANTIEPILEPTIC DRUGS
Pharmacokinetics Parameter
Half-life, Cmax, Cmin, Clearance, Volume of
Distribution
Metabolism of the drug.
Active metabolites
Drug-Drug Interactions
Inhibition or induction
Binding Characteristics
Large Clinical Studies With
Lots of Blood Levels and
Clinical Efficacy Data
TDM Needs an Analytical
Method
Requirements for an
Analytical Method
Specificity
Precision
Accuracy
Sensitivity
Reproducible
Analytically Pure and Characterized Standards.
Transferable to other sites
Analytical Standards
NIST
SRM 900
Phenytoin, phenobarbital, ethosuximide and
primidone
SRM 1599
Carbamazepine and valproic acid
TDM for AEDs PRIOR to
1990
Phenobarbital
Phenytoin (diphenylhydantoin)
Primidone
Ethosuximide
Carbamazepine
Valproic Acid
THERAPEUTIC CONCENTRATION
RANGE FOR CLASSIC AEDs
Patients with epilepsy may require more than one drug to treat
their disorder.
Some AED’s can have involved pharmacokinetics properties, e.g.,
phenytoin.
The addition of new therapy can cause pharmacokinetic changes
via enzyme induction or inhibition.
Blood levels may rise or fall causing toxicity or increased
seizures. Example: Isoniazid inhibits conversion of primidone to
phenobarbital.
Compliance
Do low blood levels of AEDs indicate non-
compliance? Not Always.
The time of sampling in relation to the last dose is
critical.
When was therapy started? Drug’s half-life and
volume of distribution will influence the steady state
blood level, e.g., flunarizine and carbamazepine.
Pharmacogenetic characteristic of the patient-fast or
slow metabolizer. If possible check urine for
metabolites
WHAT IS MEASURED?
Total drug or unbound
Depends on the percent drug bound.
Highly protein binding, Yes -Low protein binding, No
Decreases in binding for drugs that are highly bound
to plasma proteins can produce a decrease in total
plasma concentration whereas the change unbound
drug is less dramatic.
Metabolites
Some AEDs are metabolized to active metabolites.
Primidone, carbamazepine, oxcarbazepine, diazepam
mephenytoin, mephobarbital
Biological Specimens
Plasma
Serum
Cerebral Spinal Fluid
Saliva
Tears
Hair
DETERIMINNG THE THERAPEUTIC
CONCENTRATIONS OF NEW AEDs
Assay Development
Usually done by PHARMA during AED
development phase.
Plasma controlled rather than dose (mg/kg) in
phase IIB and phase III efficacy clinical trials.
Maintenance dose for a plasma level can be
calculated from clearance value of a single dose
administration.
An example is this is the NINDS flunarizine
efficacy trial. Target plasma level as 60 ng/ml.
The therapeutic concentration is best
determined under mono-therapy conditions.
ASSAY DEVELOPMENT
FOR NEW AEDs
Conclusion
TDM of the modern AEDs can be useful in
titrating patients whose epilepsy is difficult to
control and in cases of questionable compliance
and drug-drug interactions
Recommendation
Routine TDM of the newer AEDs appears not to
be useful. TDM can be of help in the titration
and maintenance of patients who are difficult to
control
Touw et al., Cost-effectiveness of TDM.
Ther Drug Monit 2005;27:10-7
PROPOSED THERAPEUTIC
CONCENTRATION LEVELS
Conclusion
TDM of the classic AEDs can be cost-effective.
Recommendation
Therapy with the classic is preferably guided by
TDM
WHEN TO USE OF AED
THERAPEUTIC DRUG MONITORING