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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