Overview of Therapeutic Drug Monitoring (TDM) process

1. Dr. Arun Sharma
Therapeutic Drug Monitoring
(TDM)

2. Overview
• TDM Introduction
• Historical aspects
• TDM in India
• Criteria for TDM
• Indications for TDM
• The TDM Process
• Clinical significance of
TDM
• Limitations
• Pharmacoeconomic
aspects of TDM
• Conclusion
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3. TDM : Introduction
• Therapeutic drug monitoring (TDM) is the
clinical practice of measuring specific drugs at
designated intervals to maintain a constant
concentration in a patient’s bloodstream,
thereby optimizing individual dosage regimens.
• In other words, TDM refers to the
individualization of drug dosage by maintaining
plasma or blood drug concentrations within a
targeted therapeutic range or window.
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4. • Therapeutic drug monitoring involves not only
measuring drug concentrations, but also the
clinical interpretation of the result.
• The goal of this process is to individualize
therapeutic regimens for optimal patient benefit.
• By combining knowledge of pharmaceutics,
pharmacokinetics and pharmacodynamics, TDM
enables the assessment of the efficacy and safety
of a particular medication in a variety of clinical
settings.
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5. • TDM is based on the principle that for some
drugs there is a close relationship between the
plasma level of the drug and its clinical effect.
• Another assumption is that drug metabolism
varies from patient to patient.
• When a precise therapeutic end point is difficult
to define, monitoring of drug levels may be of
considerable therapeutic assistance.
• Routine monitoring is however not advocated for
most drugs.
• Only clinically meaningful tests should be
performed. 5

6. • Therapeutic drug monitoring aims to promote
optimum drug treatment by maintaining serum
drug concentration within a ‘Therapeutic Range’.
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7. TDM : History
• The science of Therapeutic Drug Monitoring
grew out of the recognition that:
– Certain drugs have a narrow therapeutic range.
– In concentrations above the upper limit of the
range, the drug can be toxic.
– In concentrations below the lower limit of the
range, the drug can be ineffective.
– Not all patients have the same response at
similar doses.
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8. • These findings led to the development of Clinical
Pharmacology departments.
• However, not everyone embraced TDM testing.
Some believed that TDM testing provided little or
no value.
• Studies were initiated to determine the clinical
value of TDM testing, and in certain instances
clear clinical value was demonstrated.
• Today there are over 20 therapeutic drugs which
are routinely monitored.
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9. TDM in India
• TDM was introduced in India in mid 1980s and
last 20 years have seen its growth.
• TDM in India exists in mainly 2 settings:
–In Large teaching hospitals through Dept. of
Clinical Pharmacology.
–In Private sector (Biochemistry Labs,
dedicated CPU units in Corporate hospitals
like Apollo)
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10. Criteria for TDM
1) An appropriate analytical test for drug and active
metabolites must exist.
2) Drug should have a narrow therapeutic range.
3) Patients not showing adequate clinical response to
a drug despite being on adequate dose.
4) The therapeutic effect can not be readily assessed
by the clinical observation (e.g. anticonvulsants,
anti arrythimcs, antidepressants etc.)
5) Large individual variability in steady state plasma
concentration exits at any given dose
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11. • There are several classes of drugs commonly
monitored to ensure correct blood
concentration, including the following:
– Antiepileptics (Phenytoin, Valproic acid etc.)
– Antiarrythmics (Digitalis, lignocaine etc.)
– Antibiotics (Gentamycin, amikacin, tobramycin)
– Antineoplastics (Methotrexate)
– Antimanics (Lithium)
– Bronchodilators (Theophylline)
– Immunosuppressives (Cyclosporine)
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12. Indications for TDM
• While there may be specific individual
circumstances for TDM, most indications can be
summarized as follows:
1. Low therapeutic index.
2. Poorly defined clinical end point.
3. Non compliance.
4. Therapeutic failure.
5. Drugs with saturable metabolism.
6. Wide variation in the metabolism of drugs.
7. For diagnosis of suspected toxicity & determining
drug abuse.
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13. Indications for TDM
8. Drugs with steep dose response curve (small
increase in dose can result in a marked increase
in desired/undesired response e.g. theophylline)
9. When another drug alter the relationship
between dose & plasma concentration e.g.
plasma concentration of lithium is increased by
thiazide.
10. Renal disease (alters the relationship between
dose & the plasma concentration. Important in
case of digoxin, lithium & aminoglycoside
antibiotics.)
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14. • TDM is unnecessary when:
1) Clinical outcome is unrelated either to dose
or to plasma concentration.
2) dosage need not be individualized.
3) the pharmacological effects can be clinically.
quantified (BP, HR, Blood sugar, urine volume etc.)
4) when concentration effect relationship remains
unestablished.
5) drugs with wide therapeutic range such as beta
blockers and calcium channel blockers.
6) Hit and run drugs e.g. Omeprazole. 14

15. The TDM Process
TDM is a multidisciplinary function and requires
collaboration and good communication between
scientists, clinicians, nurses and pharmacologists.
1) Decision to request Drug level:
Decision will be based on proper reasons:
– Suspected toxicity.
– Lack of response/compliance.
– To asses therapy following change in dosage.
– Change in clinical state of patient.
– Potential drug interactions due to concomitant
medications. 15

16. 2) The Biological Sample:
• After decision is made, biological sample is
collected for to provide measurement.
• Serum or plasma samples are usually collected
for TDM.
• Serum separator tubes should be avoided as
lipophilic drugs can dissolve in gel barrier.
• Blood sample should be collected once the drug
concentration have attained steady state (SS) (at-
least 5 half lives at the current dosage regimen).
• Levels approximating SS may be reached earlier if
a loading dose has been administered (drugs
with long half lives e.g. digoxin). 16

17. • However, drugs with long half-lives should be
monitored before SS is achieved to ensure that
individuals with impaired metabolism or renal
excretion are not in the risk of developing toxicity
at the initial dosage prescribed.
• If toxicity is suspected the concentration should
be measured as soon as possible.
• Immediate assay is required if there is a poor
therapeutic control as in atrial fibrillation, when
loading dose would be useful. 17

18. • Blood samples should be collected in elimination
phase rather than absorption / distribution phases.
• Usually blood samples are collected at the end of
the dosage interval (Trough).
• For antibiotics given intravenously, Peak
concentrations (30 minutes after cessation of i.v.
infusion) are also measured.
• Usually drug concentrations are monitored in
venous blood, serum or plasma and it is important
that the appropriate matrix is assayed.
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19. • In general serum or plasma concentrations are
comparable but the blood collecting tube used is
important as few anticoagulants used are
inappropriate to few drugs and analytical
procedures.
• Whole blood must be sampled for few drugs like,
Cyclosporine A, that distributes between plasma and
erythrocytes.
• In infants, capillary blood may be collected for TDM.
• Despite extensive research examined the utility of
saliva measurements other biological fluids are not
routinely sampled.
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20. • Errors in the timing of sampling are likely
responsible for the greatest number of errors in
interpreting the results.
• Examples:
– Lithium: 12 hr sample is most precise.
– Digoxin: Make measurements at least 6 hrs after a
dose to avoid inappropriate high levels.
– Carbamazepine: Its half life is as long as 48 hrs
following a single dose. So a thorough concen-
tration taken just after a dose together with a
peak level three hrs later is ideal
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21. 3) The Request:
• Following details must be effectively
communicated to members of TDM team with a
drug assay request:
– Timing of sample
– Dosage regimen
– Patient demographics (age, sex, ethnicity etc.)
– Co-medications, if any
– Indication for monitoring
– PK and therapeutic range of drug
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22. • When a drug which is commonly measured for
TDM is suspected of causing toxicity, it is very
important for requesting clinicians to clearly
communicate the expectation of a high
concentration and need for a rapid feedback of
results.
4) Laboratory measurement:
• A quality drug assay should be performed within
a clinically useful time frame.
• The assay procedure should be a validated one
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23. • Wherever possible assay procedure should be
evaluated with an external quality assurance
program.
• Senior laboratory staff should verify the assay
results in light of clinical request.
• Ideally the results of the assay should be
available to the clinician before the next dose is
given.
• Commercial kits can be used wherever possible
and found economical, but these kits are not
available for all the drugs require TDM.
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24. • The analytical methodology employed should ideally:
1) Distinguish between compounds of similar structure
– unchanged drug and metabolites
2) Detect small amounts
3) Be simple enough to use as a routine assay
4) Be unaffected by other drugs administered
simultaneously.
• Various analytical techniques available are
Spectrophotometry and Fluorimetry, Thin layer
chromatography (TLC), HPLC and GLC, Radio Immuno
assay(RIA), Enzyme Immuno assay, Fluorescence
polarization Immunoassay (FPIA) 24

25. 5) Result communication by Laboratory:
• The assay results should be communicated as
quickly as possible once it is verified by the senior
laboratory personnel (preferably within 24 hr).
• The drug concentrations measured are generally
reported in mass or molar units .
• To relate concentration back to dose, mass units
are preferable.
• The result should clearly state the therapeutic
concentration range for the drug assayed.
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26. 6) Clinical interpretation:
• Clinical interpretation can ‘add value’ and convert
‘therapeutic measurement service’ into
‘therapeutic drug monitoring service’.
• Just relating a drug concentration to a published
therapeutic range is not an adequate interpret-
ation.
• Concentration must always be interpreted in the
light of clinical response, individual patient
demographics and dosage regimen used.
• Therapeutic ranges are available but should only
be used as a guide. 26

27. • Dosage prediction by using several softwares help
in individualizing dosage regimen.
• Special situations:
 Serum Concentrations Lower than Anticipated:
(Patient compliance, error in dosage regimen,
wrong drug product, poor bioavailability).
 Serum Concentrations Higher than Anticipated:
(Patient compliance, error in dosage regimen, poor
metabolizer, high plasma protein bounding).
 Serum Concentration Correct but Patient Does Not
Respond to Therapy: (Altered receptor sensitivity
eg, tolerance, drug interactions at receptor )
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28. 7) Therapeutic management:
• The clinician caring for a patient will modify a
drug dosage regimen in light of all available
information
• Physicians usually accept and implement
recommendations of TDM team.
• Hence, member of the TDM team with
appropriate clinical expertise should be available
to conduct a successful TDM
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29. Clinical significance of TDM
1. Maximizes efficacy
2. Avoids toxicity
3. Identifies therapeutic failure
– Non compliance, subtherapeutic dose
4. Facilitates adjustment of dosage
New dose = Old dose X Desired Css/Old Css
5. Facilitates the therapeutic effect of drug by
achieving target drug concentration
6. Identify poisoning, drug toxicity and drug abuse

30. 30
Limitations of TDM Process

31. TDM: Pharmacoeconomics
• The measurement of drug levels in body fluids
must be cost effective.
• Mungall et al showed that therapeutic drug
monitoring service offered substantial benefits
like fewer adverse reactions, shorter intensive
care unit stay and shorter overall hospital stay.
• Resources consumed by TDM are likely to be
regained by positive outcomes
• Thus, TDM is an appropriate candidate for an
economic outcomes evaluation.
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32. FREE DRUG MONITORING (FDM)
• Development of new filtration devices (equil-
ibrium dialysis, ultrafiltration, ultracentri-
fugation) has made it possible to measure free
unbound drug levels in serum.
• The advantages are that the free concentrations
is independent of changes in plasma binding and
is the pharmacologically active concentration.
• The disadvantages are that it is time consuming,
expensive and therapeutic ranges do not yet
exist for many drugs.
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33. Conclusion
• TDM may be useful for establishing initial dosing
and monitoring certain medications.
• TDM can not compensate for error in diagnosis,
poor choice of drugs, errors in dispensing and
dosages, errors in sampling, non compliance etc.
• However, when used in combination with good
clinical observation, it can lead to optimal drug
therapy with minimal side effects.
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34. • TDM data provides the clinician with greater
insight into the factors determining the patients
response to drug therapy.
• It can help to distinguish a noncompliant patient
and a patient who is a true non-responder.
• Thus, TDM is a useful adjunct in treating many
patients provided the potential pit falls and
problems are considered.
******
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35. References
 Therapeutic drug monitoring in a developing country: an overview
N J Gogtay, N A Kshirsagar, S S Dalvi Br J Clin Pharmacol. 1999
November; 48(5): 649–654. doi: 10.1046/j.1365-2125.1999.00088.x
PMCID: PMC2014358
Web link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014358/
 Therapeutic Drug Monitoring (TDM) - An Educational Guide Web link:
http://www.medical.siemens.com/siemens/en_GLOBAL/gg_diag_FBAs/files/
products_disease_states/TDM/TDM_Guide_FINAL.pdf
 Therapeutic drug monitoring D.J. Birkett, Professor of Clinical Pharmacology,
Flinders University of South Australia, Adelaide
Web link: http://www.australianprescriber.com/magazine/20/1/9/11
 Overview of Therapeutic Drug Monitoring .Ju-Seop Kang and Min-Ho Lee..
Korean Journal of Internal Medicine Vol. 24, No. 1, March 2009. pg 1-8
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