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 patients 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 Phenytoin Carbamazepine Phenobarbital Primidone Ethosuximide Valproic acid Concentration Range (umol/L) 25-50 15-45 50-130 25-50 300-600 300-600

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

Mean g/ml 24.8 21.1 5.1 49.9

Range g/ml 0.0-76.8 0.0-73.0

CV % 40.7 198.0

Phenytoin Phenobarbitone Primidone Ethosuximide

107 107 93 74

0.0-246.4 106.0 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 AEDs 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 noncompliance? Not Always. The time of sampling in relation to the last dose is critical. When was therapy started? Drugs 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 COSTEFFECTIVENESS 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 Oxcarbazepine* Vigabatrin Lamotrigine Felbamate Gabapentin Topiramate Tiagabine Levetiracetam Zonisamide Serum levels (mol/l) 50 - 140 10 - 60 125 - 250 70 - 120 15 - 60 35 - 120 45 180

Johannessen et al., 2003

RECOMMENDATIONS ON COSTEFFECTIVENESS 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 patients epileptic seizures.

AXIOM

Dont Treat the Blood Levels, Treat the Patient