APPLYING TDM TO APPLYING TDM TO ANTIEPILEPTIC DRUGSANTIEPILEPTIC DRUGS

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

Kupferberg Consultants, LLC

Retired, Chief Preclinical Pharmacology Section

Epilepsy Branch, NINDS, NIH

EPILEPSY AND SEIZURESEPILEPSY AND SEIZURES

Treatment is prophylactic and seizures Treatment is prophylactic and seizures occur at irregular timesoccur at irregular times

Clinical symptoms and signs of toxicity Clinical symptoms and signs of toxicity can also be difficult to detect and can also be difficult to detect and interpret.interpret.

Intermediate physiologic markers of Intermediate physiologic markers of clinical effects or toxicity of AEDs are not clinical effects or toxicity of AEDs are not available.available.

Optimize the clinical outcome in patients by managing their medication with the assistance of measured drug levels.Assure patient’s compliance of administrationIdentify 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.

WHY USE TDM FOR AEDsWHY USE TDM FOR AEDs

GOAL OF TDM IN THE TREATMENT GOAL OF TDM IN THE TREATMENT OF EPILEPTIC SEIZURESOF EPILEPTIC SEIZURES

TDM is an attempt to optimize the therapeutic TDM is an attempt to optimize the therapeutic effects of AEDs while minimizing the side effects of AEDs while minimizing the side effectseffects.

There is a Relationship BetweenThere is a Relationship BetweenDose, Blood Levels and Dose, Blood Levels and

Efficacy/ToxicityEfficacy/Toxicity

ASSUMPTIONS OF TDM OF AEDsASSUMPTIONS 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, Given this relationship, what has to be known?what has to be known?

THERAPEUTIC THERAPEUTIC CONCENTRATION RANGECONCENTRATION RANGE

A patient can be seizure free and have a A patient can be seizure free and have a low blood level.low blood level.

A patient can lack toxicity and have a A patient can lack toxicity and have a high blood level.high blood level.

Each patient represents a single dose Each patient represents a single dose response curve.response curve.

How is the Therapeutic How is the Therapeutic Range Determined!Range Determined!

PKPK AND AND PDPD OF THE AEDOF 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 Large Clinical Studies With Lots of Blood Levels and Lots of Blood Levels and

Clinical Efficacy DataClinical Efficacy Data

TDM Needs an Analytical TDM Needs an Analytical MethodMethod

Requirements for an Requirements for an Analytical MethodAnalytical Method

Specificity

Precision

Accuracy

Sensitivity

Reproducible

Analytically Pure and Characterized Standards.

Transferable to other sites

Analytical StandardsAnalytical StandardsNISTNIST

SRM 900Phenytoin, phenobarbital, ethosuximide and primidone

SRM 1599Carbamazepine and valproic acid

TDM for AEDs PRIOR to TDM for AEDs PRIOR to 19901990

Phenobarbital

Phenytoin (diphenylhydantoin)

Primidone

Ethosuximide

Carbamazepine

Valproic Acid

THERAPEUTIC CONCENTRATION THERAPEUTIC CONCENTRATION RANGE FOR CLASSIC AEDsRANGE FOR CLASSIC AEDs

DrugDrug

Phenytoin

Carbamazepine

Phenobarbital

Primidone

Ethosuximide

Valproic acid

Concentration Range (umol/L)Concentration Range (umol/L)

25-50

15-45

50-130

25-50

300-600

300-600

AEDs POST 1990AEDs POST 1990Felbamate (Felbatol)Lamotrigine (Lamictal)Topiramate (Topamax)Oxcarbazepine (Trileptal)Zonisamide (Zonegran)Levetiracetam (Keppra)Gabapentin (Neurontin)Pregabalin (Lyrica)Tiagabine (Gabitril)Vigabatrin (Sabrilex)

HAVE THERAPEUTIC RANGES BEENHAVE THERAPEUTIC RANGES BEENESTABLISHED FOR THE NEW AEDs?ESTABLISHED FOR THE NEW AEDs?

NOT REALLY!NOT REALLY!

Analytical Techniques for Analytical Techniques for TDM of AEDsTDM of AEDs

Spectrophotometric

Thin Layer Chromatography

Gas Chromatography

High Performance Liquid Chromatography

GC/MS

Immunoassays fluorescence polarization immunoassay, homogeneous immunoassay, enzyme immunochromatographic

QUALITY CONTROLQUALITY CONTROL

Workshop on the Determination of Workshop on the Determination of Antiepileptic Drugs in Body Fluids Antiepileptic Drugs in Body Fluids

(WODADIBOF)(WODADIBOF)

Noordwijkerhout, The Netherlands - 1972

Bethel, Bielefeld, Germany - 1974

Exeter, England- 1976

Oslo, Norway - 1979

Results Results of AED of AED Determinations Determinations in One in One Pooled Pooled Plasma Sample from 112 Plasma Sample from 112 LaboratoriesLaboratories

Drug n Mean g/ml

Range g/ml

CV %

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

InterInter--laboratory variability in laboratory variability in the quantification of new the quantification of new

generation antiepileptic drugsgeneration 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 TDMPolypharmacy 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.

ComplianceCompliance

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?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.

MetabolitesSome AEDs are metabolized to active metabolites.

Primidone, carbamazepine, oxcarbazepine, diazepam mephenytoin, mephobarbital

Biological Specimens Biological Specimens

Plasma

Serum

Cerebral Spinal Fluid

Saliva

Tears

Hair

DETERIMINNG THE THERAPEUTIC DETERIMINNG THE THERAPEUTIC CONCENTRATIONS OF NEW AEDsCONCENTRATIONS 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 ASSAY DEVELOPMENT FOR NEW FOR NEW AEDsAEDs

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 AEDsTDM and NEW AEDs

Serum level monitoring is an important issue during development of new AEDs

Guidelines for Clinical Evaluation of Antiepileptic DrugsGuidelines for Clinical Evaluation of Antiepileptic Drugs

(Epilepsia 1989;30:400(Epilepsia 1989;30:400--88))

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

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

RECOMMENDATIONS ON COSTRECOMMENDATIONS ON COST--EFFECTIVENESS FOR NEW AEDsEFFECTIVENESS FOR NEW AEDs

ConclusionTDM 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 PROPOSED THERAPEUTIC CONCENTRATION LEVELSCONCENTRATION LEVELS

DrugOxcarbazepine*VigabatrinLamotrigineFelbamateGabapentinTopiramateTiagabineLevetiracetamZonisamide

Serum levels (μmol/l)50 - 140

-10 - 60

125 - 25070 - 12015 - 60

-35 - 12045 – 180

Johannessen et al., 2003

RECOMMENDATIONS ON COSTRECOMMENDATIONS ON COST--EFFECTIVENESS FOR CLASSIC AEDsEFFECTIVENESS FOR CLASSIC AEDs

ConclusionConclusionTDM of the classic AEDs can be cost-effective.

RecommendationRecommendationTherapy with the classic is preferably guided by TDM

WHEN TO USE OF AED WHEN TO USE OF AED THERAPEUTIC DRUG MONITORINGTHERAPEUTIC DRUG MONITORING

At the initiation of drug therapyAfter 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 WHEN TO USE AED THERAPEUTIC DRUG MONITORINGDRUG MONITORING

Change in physiological statePregnancy, elevated temperature, thyroid dysfunction, loss of albumin or binding sites.

When toxicity is suspectedA 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 TDM IN CONCENTRATION CONTROLLED CLINICAL TRIALCONTROLLED 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.

PledgerPledger GW, et al. Neurology 44:183GW, et al. Neurology 44:183--6, 19946, 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.

““Don’t Treat the Blood Don’t Treat the Blood Levels, Treat the Patient”Levels, Treat the Patient”

AXIOMAXIOM