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APPLYING TDM TO

ANTIEPILEPTIC DRUGS

Harvey J. Kupferberg, Ph.D,, Pharm.D.


Kupferberg Consultants, LLC
Retired, Chief Preclinical Pharmacology Section
Epilepsy Branch, NINDS, NIH
EPILEPSY AND SEIZURES

™Treatment is prophylactic and seizures


occur at irregular times
™Clinical symptoms and signs of toxicity
can also be difficult to detect and
interpret.
™Intermediate physiologic markers of
clinical effects or toxicity of AEDs are not
available.
WHY USE TDM FOR AEDs

™ Optimize the clinical outcome in patients by


managing their medication with the assistance of
measured drug levels.
™ Assure patient’s compliance of administration
™ Identify drug-drug interactions.
™ Establish relationship between dose and blood levels
for patient.
™ Narrow therapeutic range.
™ Protein binding can be very important response in
patient response to medication.
™ Different seizure types respond differently to
medication.
GOAL OF TDM IN THE TREATMENT
OF EPILEPTIC SEIZURES

TDM is an attempt to optimize the therapeutic


effects of AEDs while minimizing the side
effects.
effects
There is a Relationship Between
Dose, Blood Levels and
Efficacy/Toxicity
ASSUMPTIONS OF TDM OF AEDs

™ The blood levels correlates better to the clinical effects


than the dose.

™ Pharmacologic requirements to fulfill the relationship.


™ AED should have a direct and reversible with an active
site.
™ Tolerance to the AED does not occur.
™ The AED should not act through a metabolite. If it does,
the metabolite should be measured.
™ The concentration of the AED at the active site is related
to the sampling site.
Given this relationship,
what has to be known?
THERAPEUTIC
CONCENTRATION RANGE
™ A patient can be seizure free and have a
low blood level.
™ A patient can lack toxicity and have a
high blood level.
™ Each patient represents a single dose
response curve.
How is the Therapeutic
Range Determined!
PK AND PD OF THE AED

™ 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

Drug Concentration Range (umol/L)


Phenytoin 25-50
Carbamazepine 15-45
Phenobarbital 50-130
Primidone 25-50
Ethosuximide 300-600
Valproic acid 300-600
AEDs POST 1990
™ Felbamate (Felbatol)
™ Lamotrigine (Lamictal)
™ Topiramate (Topamax)
™ Oxcarbazepine (Trileptal)
™ Zonisamide (Zonegran)
™ Levetiracetam (Keppra)
™ Gabapentin (Neurontin)
™ Pregabalin (Lyrica)
™ Tiagabine (Gabitril)
™ Vigabatrin (Sabrilex)
HAVE THERAPEUTIC RANGES BEEN
ESTABLISHED FOR THE NEW AEDs?
NOT REALLY!
Analytical Techniques for
TDM of AEDs
™ Spectrophotometric
™ Thin Layer Chromatography
™ Gas Chromatography
™ High Performance Liquid Chromatography
™ GC/MS
™ Immunoassays fluorescence polarization
immunoassay, homogeneous immunoassay, enzyme
immunochromatographic
QUALITY CONTROL
Workshop on the Determination of
Antiepileptic Drugs in Body Fluids
(WODADIBOF)

™Noordwijkerhout, The Netherlands - 1972


™Bethel, Bielefeld, Germany - 1974
™Exeter, England- 1976
™Oslo, Norway - 1979
Results of AED Determinations in One Pooled
Plasma Sample from 112 Laboratories

Drug n Mean Range CV


g/ml g/ml %

Phenytoin 107 24.8 0.0-76.8 40.7


Phenobarbitone 107 21.1 0.0-246.4 106.0
Primidone 93 5.1 0.0-73.0 198.0
Ethosuximide 74 49.9 0.0-836.0 195.0
Inter-laboratory variability in
the quantification of new
generation antiepileptic drugs
™ Lyophilized serum samples containing
clinically relevant concentrations of:
™ Felbamate, gabapentin, lamotrigine,
metabolite of oxcarbazepine, tiagabine,
topiramate, and vigabatrin
™ 70 laboratories participated
™ (International Heathcontrol External
Quality Assessment Scheme (EQAS)
™ HPLC assay was the most used assay
technique.
™ Accuracy was <10% for all drugs except
tiagabine.
™ Lamotrigine was the most quantified drug.
™ Interlaboratory variability in the
determination of new AEDs was comparable to
that reported with older-generation agents.
Williams, J et al, Epilepsia Vol.44, 40-5 (2003)
Polypharmacy and TDM

™ 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

™ FDA has issued new FDA-CDRH guidelines


which allow TDM assays to be developed and
marketed in parallel with new drugs
™ Commitment of AACC to help TDM assay
development
TDM and NEW AEDs

Guidelines for Clinical Evaluation of Antiepileptic Drugs


(Epilepsia 1989;30:400-8)

™ Serum level monitoring is an important issue


during development of new AEDs
“TDM is more than simply the analysis of a single
drug concentration in the blood and a report of this
number. It also comprises interpretation of the
value measured.”

Touw DJ et al. Ther. Drug Moniit. 2005;27:10-17


RECOMMENDATIONS ON COST-
EFFECTIVENESS 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

Drug Serum levels (μmol/l)


Oxcarbazepine* 50 - 140
Vigabatrin -
Lamotrigine 10 - 60
Felbamate 125 - 250
Gabapentin 70 - 120
Topiramate 15 - 60
Tiagabine -
Levetiracetam 35 - 120
Zonisamide 45 – 180

Johannessen et al., 2003


RECOMMENDATIONS ON COST-
EFFECTIVENESS FOR CLASSIC AEDs

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

™ At the initiation of drug therapy


™ After steady state levels have been achieved.
™ When seizure control has been achieved.
™ This is the reference concentration of the patient.
™ When seizure control is lost.
™ A lower plasma level might explain the increase in
seizure rate.

M.J. Eadie, Clin. Pharmacokinet. 29,1995


WHEN TO USE AED THERAPEUTIC
DRUG MONITORING

™ Change in physiological state


™ Pregnancy, elevated temperature, thyroid
dysfunction, loss of albumin or binding sites.
™ When toxicity is suspected
™ A increased plasma level might explain the
toxicity. If not, other causes must be explored.
™ Prior to the withdrawal of AED therapy.
™ A reference point if therapy must be resumed
later.
TDM IN CONCENTRATION
CONTROLLED CLINICAL TRIAL

™ Flunarizine for the control of partial seizures.


™ Randomized, double-blind, multicenter, placebo
controlled trial
™ 92 patients received concomitant PHT and CBZ.
™ Target concentration: 60 ng/ml
™ Achieved median concentration: 71 ng/ml
™ Maintenance dose: 7-138 mg/day following
loading dose. Mean dose 40 mg/day..
™ Seizure rate reduction from baseline was
statistically significant in flunarizine treated
group.

Pledger GW, et al. Neurology 44:183-6, 1994


™ In recent years, TDM has been criticized for
measuring drug levels unnecessarily or
interpreting the results incorrectly

™ TDM should be requested only on sound clinical


judgement to keep it as a valuable tool when
attempting to control the patient’s epileptic
seizures.
AXIOM

“Don’t Treat the Blood


Levels, Treat the Patient”