Theurapeutic drug monitoring theurapeutic drug monitoring theurapeutic drug monitoring

TDM

1. THERAPEUTIC DRUG MONITORINGTHERAPEUTIC DRUG MONITORING
K.P. ARUNK.P. ARUN
LECTURERLECTURER
DEPARTMENT OF PHARMACY PRACTICEDEPARTMENT OF PHARMACY PRACTICE
JSS COLLEGE OF PHARMACYJSS COLLEGE OF PHARMACY
OOTYOOTY

2. INTRODUCTIONINTRODUCTION
Clinicians routinely monitor drug pharmacodynamics by directly Clinicians routinely monitor drug pharmacodynamics by directly
measuring physiological indices of therapeutic response measuring physiological indices of therapeutic response (E.g.: (E.g.:
lipid concentration, blood glucose, BP, clotting test) lipid concentration, blood glucose, BP, clotting test)
For many drugs there is no readily available measure of effect or For many drugs there is no readily available measure of effect or
it is insufficiently sensitiveit is insufficiently sensitive
Large interindividual variation between dose and response can Large interindividual variation between dose and response can
make individualizing drug dosage difficult make individualizing drug dosage difficult

Blood Blood
ConcentrationConcentration
DoseDose
ClinicalClinical
PK VariabilityPK Variability Effect Effect
PD VariabilityPD Variability
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ADME
Receptor Interaction
And
Receptor Response

3. INTRODUCTION…INTRODUCTION…

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4. INTRODUCTION…INTRODUCTION…
In other cases it is difficult to distinguish between the progress of In other cases it is difficult to distinguish between the progress of
the disease and the pharmacological effect of the drugthe disease and the pharmacological effect of the drug
In these situations ‘Therapeutic Drug Monitoring’ becomes an In these situations ‘Therapeutic Drug Monitoring’ becomes an
essential part of clinical managementessential part of clinical management
Therapeutic drug monitoring, or TDM as it is commonly called, is Therapeutic drug monitoring, or TDM as it is commonly called, is
about about using drug serum concentrations, pharmacokinetics, and using drug serum concentrations, pharmacokinetics, and
pharmacodynamics to individualize and optimize patient pharmacodynamics to individualize and optimize patient
response to drug therapyresponse to drug therapy
Therapeutic drug monitoring aims to promote optimum drug Therapeutic drug monitoring aims to promote optimum drug
treatment by maintaining serum drug concentration within a treatment by maintaining serum drug concentration within a
‘Therapeutic Range’‘Therapeutic Range’
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5. INTRODUCTION…INTRODUCTION…
Therapeutic drug monitoring is a practice applied to a small group Therapeutic drug monitoring is a practice applied to a small group
of drugs in which of drugs in which there is a direct relationship between there is a direct relationship between
concentration and responseconcentration and response
Serum concentrations are used as the Serum concentrations are used as the most practical intermediate most practical intermediate
endpoint to gauge treatment when there is no clearly observable endpoint to gauge treatment when there is no clearly observable
therapeutic or toxic endpointtherapeutic or toxic endpoint
‘‘Therapeutic Range’ Therapeutic Range’ represents a range of drug concentrations represents a range of drug concentrations
within which the within which the probabilityprobability of a desired clinical response is of a desired clinical response is
relatively high and the relatively high and the probabilityprobability of unacceptable toxicity is of unacceptable toxicity is
relatively lowrelatively low
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6. INTRODUCTION…INTRODUCTION…
Some patients have toxic reactions within the therapeutic range Some patients have toxic reactions within the therapeutic range
The most common reasons for using a serum drug level as a guide The most common reasons for using a serum drug level as a guide
are to provide additional information to be used in conjunction are to provide additional information to be used in conjunction
with other clinical data to assist in determining patient status to with other clinical data to assist in determining patient status to
provide a basis for individualizing patient dosage regimenprovide a basis for individualizing patient dosage regimen
Therapeutic drug monitoring blends knowledge of therapeutics, Therapeutic drug monitoring blends knowledge of therapeutics,
pharmacology, pharmacokinetics, laboratory technology, and pharmacology, pharmacokinetics, laboratory technology, and
clinical medicine and applies it to certain drugs that require clinical medicine and applies it to certain drugs that require
determination of patient specific dosage regimens to maximize determination of patient specific dosage regimens to maximize
therapeutic effectiveness while minimizing toxicitytherapeutic effectiveness while minimizing toxicity
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7. TDM will be Useful If…TDM will be Useful If…
1) The drug in question has a narrow therapeutic range1) The drug in question has a narrow therapeutic range
2) A direct relationship exists between the drug or drug metabolite 2) A direct relationship exists between the drug or drug metabolite
levels in plasma and the pharmacological or toxic effectslevels in plasma and the pharmacological or toxic effects
3) The therapeutic effect can not be readily assessed by the clinical 3) The therapeutic effect can not be readily assessed by the clinical
observationobservation
4) Large individual variability in steady state plasma concentration 4) Large individual variability in steady state plasma concentration
exits at any given doseexits at any given dose
5) Appropriate analytic techniques are available to determine the 5) Appropriate analytic techniques are available to determine the
drug and metabolite levelsdrug and metabolite levels
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8. TDM is Unnecessary If…TDM is Unnecessary If…
1) Clinical outcome is unrelated either to dose or to plasma 1) Clinical outcome is unrelated either to dose or to plasma
concentrationconcentration
2) Dosage need not be individualized2) Dosage need not be individualized
3) The pharmacological effects can be clinically quantified3) The pharmacological effects can be clinically quantified
4) When concentration effect relationship remains unestablished4) When concentration effect relationship remains unestablished
5) Drugs with wide therapeutic range such as beta blockers and 5) Drugs with wide therapeutic range such as beta blockers and
calcium channel blockerscalcium channel blockers
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9. The TDM ProcessThe TDM Process
1. Reasons for Requesting TDM:1. Reasons for Requesting TDM:
1. Low therapeutic index1. Low therapeutic index
2. Poorly defined clinical end point2. Poorly defined clinical end point
3. Non compliance3. Non compliance
4. Therapeutic failure – 4. Therapeutic failure – Sub therapeutic Concentration?Sub therapeutic Concentration?
5. Drugs with saturable metabolism5. Drugs with saturable metabolism
6. Wide variation in the metabolism of drugs6. Wide variation in the metabolism of drugs
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10. The TDM Process…The TDM Process…
1. Reasons for Requesting TDM…1. Reasons for Requesting TDM…
7. Major organ failure7. Major organ failure
8. Prevention of adverse drug effects8. Prevention of adverse drug effects
9. Toxicity suspected – 9. Toxicity suspected – Toxic Concentration?Toxic Concentration?
10. Change in clinical state of the patient10. Change in clinical state of the patient
11. Assess therapy following a change in dosage regimen11. Assess therapy following a change in dosage regimen
12. Potential drug interaction due to change in co-medication12. Potential drug interaction due to change in co-medication
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11. The TDM ProcessThe TDM Process
2. The Biological Sample:2. The Biological Sample:
Once the decision to monitor the concentration of the Once the decision to monitor the concentration of the
therapeutic drug has been made, it is important that the therapeutic drug has been made, it is important that the
biological sample is collected which will provide a biological sample is collected which will provide a clinically clinically
meaningful measurementmeaningful measurement
Blood sample should be collected once the drug concentration Blood sample should be collected once the drug concentration
have attained steady state (at-least 5 half lives at the current have attained steady state (at-least 5 half lives at the current
dosage regimen)dosage regimen)
Levels approximating SS may be reached earlier if a loading dose Levels approximating SS may be reached earlier if a loading dose
has been administered (drugs with long half lives)has been administered (drugs with long half lives)
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12. The TDM ProcessThe TDM Process
2. The Biological Sample… 2. The Biological Sample…
However, drugs with long half-lives should be monitored before However, drugs with long half-lives should be monitored before
SS is achieved to ensure that individuals with impaired SS is achieved to ensure that individuals with impaired
metabolism or renal excretion are not in the risk of developing metabolism or renal excretion are not in the risk of developing
toxicity at the initial dosage prescribedtoxicity at the initial dosage prescribed
If toxicity is suspected the concentration should be measured as If toxicity is suspected the concentration should be measured as
soon as possiblesoon as possible
Immediate assay is required if there is a poor therapeutic control Immediate assay is required if there is a poor therapeutic control
as in atrial fibrillation, when loading dose would be usefulas in atrial fibrillation, when loading dose would be useful

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13. The TDM ProcessThe TDM Process
2. The Biological Sample… 2. The Biological Sample…
Absorption is variable after oral drug administration and blood samples Absorption is variable after oral drug administration and blood samples
should be collected in should be collected in elimination phase elimination phase rather than absorption / rather than absorption /
distribution phases distribution phases
Usually blood samples are collected at the end of the dosage interval Usually blood samples are collected at the end of the dosage interval
(Trough) (Trough)
For antibiotics given intravenously, For antibiotics given intravenously, PeakPeak concentrations (30 minutes after concentrations (30 minutes after
cessation of i.v. infusion) are also measured cessation of i.v. infusion) are also measured
Usually drug concentrations are monitored in venous blood, serum or Usually drug concentrations are monitored in venous blood, serum or
plasma and it is important that the appropriate matrix is assayedplasma and it is important that the appropriate matrix is assayed

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14. The TDM ProcessThe TDM Process
2. The Biological Sample… 2. The Biological Sample…
In general serum or plasma concentrations are comparable but the blood In general serum or plasma concentrations are comparable but the blood
collecting tube used is important as few anticoagulants used are inappropriate collecting tube used is important as few anticoagulants used are inappropriate
to few drugs and analytical procedures to few drugs and analytical procedures
Whole blood must be sampled for few drugs like, Cyclosporine A, that Whole blood must be sampled for few drugs like, Cyclosporine A, that
distributes between plasma and erythrocytesdistributes between plasma and erythrocytes
In infants, capillary blood may be collected for TDM In infants, capillary blood may be collected for TDM
Despite extensive research examined the utility of saliva measurements other Despite extensive research examined the utility of saliva measurements other
biological fluids are not routinely sampledbiological fluids are not routinely sampled

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15. The TDM ProcessThe TDM Process
3. The Request:3. The Request:
Patient demographics are critically important so that the contribution of Patient demographics are critically important so that the contribution of
age, disease state, ethnicity, etc to interindividual variation in PK and PD age, disease state, ethnicity, etc to interindividual variation in PK and PD
can be consideredcan be considered
These details must be effectively communicated to the members of TDM These details must be effectively communicated to the members of TDM
team with a drug assay request team with a drug assay request
When a drug which is commonly measured for TDM is suspected of When a drug which is commonly measured for TDM is suspected of
causing toxicity, it is very important for requesting clinicians to clearly causing toxicity, it is very important for requesting clinicians to clearly
communicate the expectation of a high concentration and need for a communicate the expectation of a high concentration and need for a
rapid feedback of resultsrapid feedback of results

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16. The TDM ProcessThe TDM Process
3. The Request… 3. The Request…

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17. The TDM ProcessThe TDM Process
3. The Request… 3. The Request…

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18. The TDM ProcessThe TDM Process
3. The Request… 3. The Request…

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19. The TDM ProcessThe TDM Process
4. Laboratory Measurement:4. Laboratory Measurement:
 Ideally a quality drug assay must be performed within a clinically useful time Ideally a quality drug assay must be performed within a clinically useful time
frameframe
The assay procedure should be a validated one The assay procedure should be a validated one (accuracy, precision, (accuracy, precision,
sensitivity, specificity, limit of detection, limit of quantification, linear sensitivity, specificity, limit of detection, limit of quantification, linear
dynamic range, reproducibility, repeatability, robustness)dynamic range, reproducibility, repeatability, robustness)
Wherever possible assay procedure should be evaluated with an external Wherever possible assay procedure should be evaluated with an external
quality assurance programquality assurance program
Senior laboratory staff should verify the assay results in light of clinical Senior laboratory staff should verify the assay results in light of clinical
requestrequest

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20. The TDM ProcessThe TDM Process
4. Laboratory Measurement…4. Laboratory Measurement…
 Ideally the results of the assay should be available to the clinician before the Ideally the results of the assay should be available to the clinician before the
next dose is givennext dose is given
Commercial kits can be used wherever possible and found economical, but Commercial kits can be used wherever possible and found economical, but
these kits are not available for all the drugs require TDMthese kits are not available for all the drugs require TDM
The analytical methodology employed should ideally: The analytical methodology employed should ideally:
1) Distinguish between compounds of similar structure – unchanged drug and 1) Distinguish between compounds of similar structure – unchanged drug and
metabolites metabolites
2) Detect small amounts 2) Detect small amounts
3) Be simple enough to use as a routine assay and 3) Be simple enough to use as a routine assay and
4) Be unaffected by other drugs administered simultaneously4) Be unaffected by other drugs administered simultaneously

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21. The TDM ProcessThe TDM Process
4. Laboratory Measurement…4. Laboratory Measurement…
 Various analytical techniques available for TDM are Various analytical techniques available for TDM are
Spectrophotometry and FluorimetrySpectrophotometry and Fluorimetry
Thin layer chromatographyThin layer chromatography
HPLC and GLCHPLC and GLC
Radio Immuno assayRadio Immuno assay
Enzyme Immuno assay Enzyme Immuno assay
Fluorescence polarization ImmunoassayFluorescence polarization Immunoassay
Some times, the drug’s metabolite(s) and or some endogenous compounds Some times, the drug’s metabolite(s) and or some endogenous compounds
or drugs with similar structures can cross react, resulting in either a falsely or drugs with similar structures can cross react, resulting in either a falsely
elevated or decreased assayed drug concentration reading and that should elevated or decreased assayed drug concentration reading and that should
be avoidedbe avoided

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22. The TDM ProcessThe TDM Process
5. Communication of the results by Laboratory: 5. Communication of the results by Laboratory:
 The assay results should be communicated as quickly as possible The assay results should be communicated as quickly as possible
once it is verified by the senior laboratory personnelonce it is verified by the senior laboratory personnel
The drug concentrations measured are generally reported in The drug concentrations measured are generally reported in massmass or or
molarmolar units units
To relate concentration back to dose, mass units are preferableTo relate concentration back to dose, mass units are preferable
But, since most of the assays are done by biochemical methods, But, since most of the assays are done by biochemical methods,
results may be in molar units and the laboratory should be able to results may be in molar units and the laboratory should be able to
readily convert mass and molar units from one anotherreadily convert mass and molar units from one another

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23. The TDM ProcessThe TDM Process
5. Communication of the results by Laboratory…5. Communication of the results by Laboratory…
 The result should clearly state the therapeutic concentration range The result should clearly state the therapeutic concentration range
for the drug assayedfor the drug assayed
It must be remembered that different indications for therapy, age It must be remembered that different indications for therapy, age
or ethnic differences in PK or PD could result in different or ethnic differences in PK or PD could result in different
therapeutic ranges being appropriate for different population therapeutic ranges being appropriate for different population
groupsgroups
Hence, critical assessment of the original literatures and consensus Hence, critical assessment of the original literatures and consensus
recommendations for therapeutic ranges should be encouraged recommendations for therapeutic ranges should be encouraged

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24. The TDM ProcessThe TDM Process
6. Clinical Interpretation: 6. Clinical Interpretation:
 Clinical interpretation can ‘add value’ and convert ‘therapeutic Clinical interpretation can ‘add value’ and convert ‘therapeutic
measurement service’ into ‘therapeutic drug monitoring service’ measurement service’ into ‘therapeutic drug monitoring service’
Just relating a drug concentration to a published therapeutic Just relating a drug concentration to a published therapeutic
range is not an adequate interpretationrange is not an adequate interpretation
The information required to interpret the drug concentration The information required to interpret the drug concentration
include: include:
Time at which blood sample takenTime at which blood sample taken
Time at which dose is givenTime at which dose is given
Dosage regimen (Dose, Duration, Dosage Form)Dosage regimen (Dose, Duration, Dosage Form)
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25. The TDM ProcessThe TDM Process
6. Clinical Interpretation…6. Clinical Interpretation…
Patient demographic (sex, age, concomitant disease, ethnicity, etc)Patient demographic (sex, age, concomitant disease, ethnicity, etc)
Co medicationsCo medications
Indications for monitoringIndications for monitoring
PK and therapeutic range of the drugPK and therapeutic range of the drug
Dosage prediction by using several softwares help in individualizing dosage Dosage prediction by using several softwares help in individualizing dosage
regimenregimen
However, individualized dosage predictions using Bayesian techniques is very However, individualized dosage predictions using Bayesian techniques is very
useful tool for teaching clinical pharmacokinetics concepts and TDM for useful tool for teaching clinical pharmacokinetics concepts and TDM for
learnerslearners

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26. The TDM ProcessThe TDM Process
6. Clinical Interpretation…6. Clinical Interpretation…
For drugs with linear kinetics the following formula may be usedFor drugs with linear kinetics the following formula may be used
New Dose = Old Dose x Desired Concentration / Old ConcentrationNew Dose = Old Dose x Desired Concentration / Old Concentration
Pharmacokinetic Evaluation of Serum Drug ConcentrationsPharmacokinetic Evaluation of Serum Drug Concentrations
Serum Concentrations Lower than Anticipated
    
Serum Concentrations Lower than Anticipated
    
Patient compliance
  
Patient compliance
  
Error in dosage regimen
  
Error in dosage regimen
  
Wrong drug product (controlled-release instead of immediate-Wrong drug product (controlled-release instead of immediate-
release)
  
release)
  
Poor bioavailability
  
Poor bioavailability
  
Rapid elimination (efficient metabolizer)
  
Rapid elimination (efficient metabolizer)
  
Reduced plasma protein binding
  
Reduced plasma protein binding
  
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27. The TDM ProcessThe TDM Process
6. Clinical Interpretation…6. Clinical Interpretation…
Enlarged apparent volume of distribution
  
Enlarged apparent volume of distribution
  
Steady state not reached
  
Steady state not reached
  
Timing of blood sample
  
Timing of blood sample
  
Improving renal/hepatic function
  
Improving renal/hepatic function
  
Drug interaction due to stimulation of elimination enzyme Drug interaction due to stimulation of elimination enzyme
autoinduction
  
autoinduction
  
Changing hepatic blood flowChanging hepatic blood flow

Serum Concentrations Higher than Anticipated Serum Concentrations Higher than Anticipated  
 
 
 
  
Patient compliance
  
Patient compliance
  
Error in dosage regimen
  
Error in dosage regimen
  

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28. The TDM ProcessThe TDM Process
6. Clinical Interpretation…6. Clinical Interpretation…
Wrong drug product (immediate release instead of controlled release) Wrong drug product (immediate release instead of controlled release)
 
 
 
 
Rapid bioavailability
  
Rapid bioavailability
  
Smaller than anticipated apparent volume of distribution
  
Smaller than anticipated apparent volume of distribution
  
Slow elimination (poor metabolizer)
  
Slow elimination (poor metabolizer)
  
Increased plasma protein binding
  
Increased plasma protein binding
  
Deteriorating renal/hepatic function
  
Deteriorating renal/hepatic function
  
Drug interaction due to inhibition of eliminationDrug interaction due to inhibition of elimination
Serum Concentration Correct but Patient Does Not Respond to Therapy
    
Serum Concentration Correct but Patient Does Not Respond to Therapy
    
Altered receptor sensitivity (eg, tolerance)
  
Altered receptor sensitivity (eg, tolerance)
  
Drug interaction at receptor site
 
Drug interaction at receptor site
 

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29. The TDM ProcessThe TDM Process
For drugs with linear kinetics the following formula may be usedFor drugs with linear kinetics the following formula may be used
New Dose = Old Dose x Desired Concentration / Old ConcentrationNew Dose = Old Dose x Desired Concentration / Old Concentration
7. Therapeutic Management: 7. Therapeutic Management:
The clinician caring for a patient will modify a drug dosage regimen in light of all The clinician caring for a patient will modify a drug dosage regimen in light of all
available informationavailable information
If the members of the TDM team are well respected, many physicians will accept If the members of the TDM team are well respected, many physicians will accept
and implement their recommendations for dosage adjustment, and seek their and implement their recommendations for dosage adjustment, and seek their
further advicefurther advice
Hence, member of the TDM team with appropriate clinical expertise should be Hence, member of the TDM team with appropriate clinical expertise should be
available to conduct a successful TDM available to conduct a successful TDM

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30. Limitations of TDM ProcessLimitations of TDM Process
Scientific accuracy of the drug assaysScientific accuracy of the drug assays
Laboratory variability in reportingLaboratory variability in reporting
Limited accessibility and infrastructure facilities Limited accessibility and infrastructure facilities
Validity of suggested target rangesValidity of suggested target ranges
Lack of training and skillsLack of training and skills
Cost involvedCost involved

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