THERAPEUTIC DRUG

MONITORING,DETERMINATION OF

RATE CONSTANT &PLOTS OF

DRUG DISTRIBUTION

PRESENTED BYB.SUMANRegNo.256212886007PHARMACEUTICS

CONTENTS

INTRODUCTIONCRITERIAREASONSPROCEDURECLINICAL INTERPRETATIONFACTORS AFFECTINGEXAMPLESPROBLEMS

2.DETERMINATON OF RATE CONSTANT3.DIFFERENT PLOTS OF DRUG DISTRIBUTION

1.TDM

Therapeutic drug monitoring ismeasurement of drug concentrations in the blood or plasma that facilitates adjustment of dosage to produce a desired response

Therapeutic drug monitoring aims topromote optimum drug treatment bymaintaining serum drug concentrationwithin a ‘Therapeutic Range’

DEFINITION

Clinicians routinely monitor drug pharmacodynamics bydirectly measuring physiological indices of therapeuticresponse (E.g.: blood glucose, BP, clotting test)For many drugs there is no readily available measure ofeffect or it is insufficiently sensitive

Large interindividual variation between dose and responsecan make individualizing drug dosage difficult

INTRODUCTION

DOSE

AbsoptionDistributionMetabolismElimination

Receptor interaction &response

Clinical effect

Pharmacokinetics variability

Pharmacodynamic variability

In other cases it is difficult to distinguish betweenthe progress of the disease and the pharmacologicaleffect of the drug

In these situations ‘Therapeutic Drug Monitoring’becomes an essential part of clinical management

Therapeutic drug monitoring, or TDM as it iscommonly called, is about using drug serumconcentrations, pharmacokinetics, andpharmacodynamics to individualize and optimizepatient response to drug therapy

•Therapeutic drug monitoring is a practice applied to asmall group of drugs in which there is a directrelationship between concentration and response

•Serum concentrations are used as the most practicalintermediate endpoint to gauge treatment whenthere is no clearly observable therapeutic or toxicendpoint

•‘Therapeutic Range’ represents a range of drugconcentrations within which the probability of adesired clinical response is relatively high and theprobability of unacceptable toxicity is relatively low

• Therapeutic Index is defined as the ratio between the average effective dose and the average lethal dose. It is an extremely close margin between an effective concentration of a therapeutic drug in the blood and a fatal concentration.

The drug in question has a narrow therapeutic range

A direct relationship exists between the drug or drugmetabolite levels in plasma and the pharmacological ortoxic effects

The therapeutic effect can not be readily assessed by theclinical observation

Large individual variability in steady state plasmaconcentration exists at any given dose

Appropriate analytic techniques are available todetermine the drug and metabolite levels

TDM will be Useful If…

1) Clinical outcome is unrelated either to dose or toplasma concentration

2) Dosage need not be individualized

3) The pharmacological effects can be clinicallyquantified

4) When concentration effect relationship remainsunestablished

5) Drugs with wide therapeutic range such as betablockers and calcium channel blockers

TDM is Unnecessary If…

1. Reasons for Requesting TDM: Low therapeutic index

Poorly defined clinical end point

Non compliance

Therapeutic failure – Sub therapeuticConcentration?

Wide variation in the metabolism of drugs

1. Reasons for Requesting TDM… Major organ failure

Prevention of adverse drug effects

Toxicity suspected – Toxic Concentration?

Change in clinical state of the patient

Assess therapy following a change in dosageregimen

Potential drug interaction due to change inco-medication

2.The Biological Sample:

• Once the decision to monitor the concentration ofthe therapeutic drug has been made, it is importantthat the biological sample is collected which willprovide a clinically meaningful measurement.

• Blood sample should be collected once the drugconcentration have attained steady state (at-least 5half lives at the current dosage regimen).

• Levels approximating SS may be reached earlier if aloading dose has been administered (drugs withlong half lives).

TDM PROCESS

2. The Biological Sample…• However, drugs with long half-lives

should be monitored before SS isachieved to ensure that individuals withimpaired metabolism or renal excretionare not in the risk of developing toxicityat the initial dosage prescribed

• If toxicity is suspected the concentrationshould be measured as soon as possible

2. The Biological Sample…• Absorption is variable after oral drug administration

and blood samples should be collected in eliminationphase rather than absorption phase

• Usually blood samples are collected at the end of thedosage interval (Trough)

• For antibiotics given intravenously, Peakconcentrations (30 minutes after cessation of i.v.infusion) are also measured

• Usually drug concentrations are monitored in venousblood, serum or plasma

2. The Biological Sample… In general serum or plasma concentrations are

comparable but the blood collecting tube used isimportant as few anticoagulants used areinappropriate to few drugs and analytical procedures

Whole blood must be sampled for few drugs like,Cyclosporine A, that distributes between plasma anderythrocytes

Patient demographics are critically important so thatthe contribution of age, disease state, etc tointerindividual variation in PK and PD can beconsidered

3. The Request:

These details must be effectivelycommunicated to the members of TDMteam with a drug assay request

When a drug which is commonly measuredfor TDM is suspected of causing toxicity, itis very important for requesting cliniciansto clearly communicate the expectation ofa high concentration and need for a rapidfeedback of results

4. Laboratory Measurement:

The assay procedure should be a validatedone (accuracy, precision, sensitivity,specificity,linearrange,reproducibility,repeatability, robustness)

Wherever possible assay procedure shouldbe evaluated with an external qualityassurance program

4. Laboratory Measurement…

Ideally the results of the assay should beavailable to the clinician before the next dose isgiven

The analytical methodology employed shouldideally:

1) Distinguish between compounds of similarstructure – unchanged drug and metabolites2) Detect small amounts3) Be simple enough to use as a routine assay4)Be unaffected by other drugs administered

TDM are Various analytical techniques available for•Spectrophotometry and Fluorimetry•Thin layer chromatography•HPLC and GLC•Radio Immuno assay•Enzyme Immuno assay•Fluorescence polarization Immunoassay

Some times, the drug’s metabolite(s) and or someendogenous compounds or drugs with similar structurescan cross react, resulting in either a falsely elevated ordecreased assayed drug concentration reading and thatshould be avoided

4. Laboratory Measurement

• The assay results should be communicated as quicklyas possible once it is verified by the senior laboratorypersonnel

•The drug concentrations measured are generallyreported in mass or molar units

•But, since most of the assays are done by biochemicalmethods, results may be in molar units and thelaboratory should be able to readily convert mass andmolar units from one another

5. Communication of the results byLaboratory:

5. Communication of the results byLaboratory…

The result should clearly state the therapeuticconcentration range for the drug assayedIt must be remembered that different indications fortherapy, age or ethnic differences in PK or PD couldresult in different therapeutic ranges being appropriatefor different population groupsHence, critical assessment of the original literaturesand consensus recommendations for therapeuticranges should be encouraged

The information required to interpret the drugconcentration include:Time at which blood sample takenTime at which dose is givenDosage regimen (Dose, Duration, Dosage Form)

6. Clinical Interpretation:

Patient demographic (sex, age, concomitantdisease, ethnicity, etc)Co medicationsIndications for monitoringPK and therapeutic range of the drug

Serum Concentrations Higher thanAnticipated

•Patient compliance•Error in dosage regimen•Wrong drug product (immediate release insteadof controlled release)•Rapid bioavailability•Smaller than anticipated apparent volume ofdistribution•Slow elimination (poor metabolizer)•Increased plasma protein binding•Deteriorating renal/hepatic function•Drug interaction due to inhibition of elimination

FACTORS AFFECTING SDC

1. Disease states: renal, liver, cardiac2. Habits: diet, smoking, drinking3. Pregnancy, age, weight4. Non-compliance5. Electrolyte balance : Digoxin vs K+ & Ca++

6. Drug interactions7. Plasma protein binding8. Bioavailability9. Sampling time

COMMONLY MONITORED DRUGS

Bronchodilators: Theophylline Antibiotics : Aminoglycosides - Gentamicin,Amikacin Others - Vancomycin Immunosuppressants: Cyclosporine Anticancers: Methotrexate

COMMONLY MONITORED DRUGS

Antiepileptics: Phenobarbital, Phenytoin,Carbamazepine, Valproate

Cardiac Drugs : Digoxin*, Procainamide, Lidocaine

Psychoactive Drugs: Lithium,

TCA

Analgesics: Aspirin, Paracetamol

Hospital personnel do not know the existence of TDM service

Physicians do not understand the principles, benefits, and the limitations of TDM service

Inappropriate sampling times

Insufficient patient’s history and othernecessary data

No consultation when problems arise

PROBLEMS OF TDM SERVICE

:

DETERMINATION OF RATE CONSTANT

d

r

PLOTS OF DRUG DISTRIBUTION

Scatchard plot

N

Klotz plot

Hitchcock plot

References:-Biopharmaceutics and pharmacokinetics, D.M.BRAHMANKAR pg no 134-136.

Best practice in therapeutic drug monitoringAnnette S. Gross Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards NSW 2065, Australia.

THE THERAPEUTIC DRUG MONITORING AS A BASISFOR INDIVIDUALIZING PATIENT DOSAGE REGIMEN, Journal of Health Sciences Management and Public Health, Jozef Novotný, Tomáš Èech1