Therapeutic Drug Monitoring

RVS Chaitanya Koppala

Assistant professor
Lovely Professional Univeristy
 OVERVIEW
TDM introduction
Historical aspects in india
TDM in india
Criteria for TDM
Indication for TDM
The TDM process
Clinical significance of TDM
Limitations
Pharmcoeconomics of TDM
Conclusion
 Introduction

• Therapeutic drug monitoring is a clinical practices of measuring of

drugs at designated intervals to maintain a constant concentration in
patient’s blood stream, there by optimizing individual dosage regimen
• In other words , TDM refers to individualization of drug dosage by
maintaining plasma or blood drug concentrations within a targeted
therapeutic window or range
• TDM not only involves measuring drug concentration but also clinical
interpretations of the result.
• TDM based on principle that for some drugs there is a close relationship
between plasma levels of the drugs and its clinical effects
• Another assumption is that drug metabolism also varies from patient to
patient
• The goal of this processes is to individualize therapeutic regimens for
optimal patient benefits
• TDM enables the assessment of the efficacy and safety of a particular
medication in a variety of clinical settings.
• Therapeutic drug monitoring aims to promote optimum drug treatment
by maintaining serum drug concentration within a ‘Therapeutic Range’
 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
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
 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)
 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 cannot be readily assessed by the clinical
observation (e.g. anticonvulsants, antiarrythimcs, antidepressants
etc.)
5. Large individual variability in steady state plasma concentration
exits at any given dose
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)
 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.
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.)
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.
 The TDM Process
Decision to request drug level

Biological sample

The request

Laboratory measurement

Result communication by laboratory

Clinical interpretation

Therapeutic management
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 assess therapy following change in dosage.
Change in clinical state of patient.
Potential drug interactions due to concomitant medications.
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).
• 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.

• 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.
Errors in the timing of sampling are likely responsible for the greatest
number of errors in interpreting the results.
Examples:
– Lithium: 12 hour 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 concentration taken just after a dose together with a
peak level three hours later is ideal
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
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
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.
The analytical methodology employed should ideally:
Distinguish between compounds of similar structure – unchanged drug and
metabolites
Detect small amounts
Be simple enough to use as a routine assay
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)
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.
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 interpretation.

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

1. Dosage prediction by using several softwares help in individualizing
dosage regimen.

1. 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 )
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
 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
Limitations of TDM Process
 TDM: Pharmacoeconomics
1. The measurement of drug levels in body fluids must be cost effective.

2. 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.

3. Resources consumed by TDM are likely to be regained by positive outcomes

4. Thus, TDM is an appropriate candidate for an economic outcomes evaluation.

 FREE DRUG MONITORING (FDM)

Development of new filtration devices (equilibrium dialysis, ultrafiltration,

ultracentrifugation) 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
 therapeutic ranges do not yet exist for many drugs.
 Conclusion

1. TDM may be useful for establishing initial dosing and monitoring

certain medications.

2. TDM can not compensate for error in diagnosis, poor choice of

drugs, errors in dispensing and dosages, errors in sampling, non
compliance etc.

3. However, when used in combination with good clinical observation,

it can lead to optimal drug therapy with minimal side effects.
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.
Reference: