This document discusses therapeutic drug monitoring (TDM), including its definition, introduction, criteria for when it is useful/unnecessary, and process. TDM involves measuring drug concentrations in blood/plasma to help adjust dosages to a desired therapeutic range. It is especially useful for drugs with a narrow therapeutic index or large interindividual variability. The TDM process involves collecting a biological sample at steady state, requesting a lab analysis, the lab measuring the drug level using an appropriate analytical technique, communicating the results along with the therapeutic range, and the clinician interpreting the level based on dosage and patient factors. Commonly monitored drugs and some problems with TDM services are also mentioned.

1. THERAPEUTIC DRUG
MONITORING,DETERMINATION OF
RATE CONSTANT &PLOTS OF
DRUG DISTRIBUTION
PRESENTED BY
B.SUMAN
RegNo.256212886007
PHARMACEUTICS

2. CONTENTS
1.TDM
INTRODUCTION
CRITERIA
REASONS
PROCEDURE
CLINICAL INTERPRETATION
FACTORS AFFECTING
EXAMPLES
PROBLEMS
2.DETERMINATON OF RATE CONSTANT
3.DIFFERENT PLOTS OF DRUG DISTRIBUTION

3. DEFINITION
Therapeutic drug monitoring is
measurement of drug concentrations in the
blood or plasma that facilitates adjustment
of dosage to produce a desired response
Therapeutic drug monitoring aims to
promote optimum drug treatment by
maintaining serum drug concentration
within a ‘Therapeutic Range’

4. INTRODUCTION
Clinicians routinely monitor drug pharmacodynamics by
directly measuring physiological indices of therapeutic
response (E.g.: blood glucose, BP, clotting test)
For many drugs there is no readily available measure of
effect or it is insufficiently sensitive
Large interindividual variation between dose and response
can make individualizing drug dosage difficult
DOSE
Absoption
Distribution
Metabolism
Elimination
Receptor interaction
&response
Clinical
effect
Pharmacokinetics
variability
Pharmacodynamic
variability

5. In other cases it is difficult to distinguish between
the progress of the disease and the pharmacological
effect of the drug
In these situations ‘Therapeutic Drug Monitoring’
becomes an essential part of clinical management
Therapeutic drug monitoring, or TDM as it is
commonly called, is about using drug serum
concentrations, pharmacokinetics, and
pharmacodynamics to individualize and optimize
patient response to drug therapy

6. •Therapeutic drug monitoring is a practice applied to a
small group of drugs in which there is a direct
relationship between concentration and response
•Serum concentrations are used as the most practical
intermediate endpoint to gauge treatment when
there is no clearly observable therapeutic or toxic
endpoint
•‘Therapeutic Range’ represents a range of drug
concentrations within which the probability of a
desired clinical response is relatively high and the
probability of unacceptable toxicity is relatively low

7. • 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.

8. TDM will be Useful If…
 The drug in question has a narrow therapeutic range
 A direct relationship exists between the drug or drug
metabolite levels in plasma and the pharmacological or
toxic effects
 The therapeutic effect can not be readily assessed by the
clinical observation
 Large individual variability in steady state plasma
concentration exists at any given dose
 Appropriate analytic techniques are available to
determine the drug and metabolite levels

9. TDM is Unnecessary If…
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
4) When concentration effect relationship remains
unestablished
5) Drugs with wide therapeutic range such as beta
blockers and calcium channel blockers

10. 1. Reasons for Requesting TDM:
 Low therapeutic index
 Poorly defined clinical end point
 Non compliance
 Therapeutic failure – Sub therapeutic
Concentration?
 Wide variation in the metabolism of drugs

11. 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 dosage
regimen
 Potential drug interaction due to change in
co-medication

12. TDM PROCESS
2.The Biological Sample:
• Once the decision to monitor the concentration of
the therapeutic drug has been made, it is important
that the biological sample is collected which will
provide a clinically meaningful measurement.
• Blood sample should be collected once the drug
concentration have attained steady state (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).

13. 2. The Biological Sample…
• 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

14. 2. The Biological Sample…
• Absorption is variable after oral drug administration
and blood samples should be collected in elimination
phase rather than absorption phase
• 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

15. 2. The Biological Sample…
 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
 Patient demographics are critically important so that
the contribution of age, disease state, etc to
interindividual variation in PK and PD can be
considered

16. 3. The Request:
These details must be effectively
communicated to the members of TDM
team with a drug assay request
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

17. 4. Laboratory Measurement:
The assay procedure should be a validated
one (accuracy, precision, sensitivity,
specificity,linearrange,reproducibility,
repeatability, robustness)
Wherever possible assay procedure should
be evaluated with an external quality
assurance program

18. 4. Laboratory Measurement…
 Ideally the results of the assay should be
available to the clinician before the next dose is
given
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

19. 4. Laboratory Measurement
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 some
endogenous compounds or drugs with similar structures
can cross react, resulting in either a falsely elevated or
decreased assayed drug concentration reading and that
should be avoided

20. 5. Communication of the results by
Laboratory:
• The assay results should be communicated as quickly
as possible once it is verified by the senior laboratory
personnel
•The drug concentrations measured are generally
reported in mass or molar units
•But, since most of the assays are done by biochemical
methods, results may be in molar units and the
laboratory should be able to readily convert mass and
molar units from one another

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

22. 6. Clinical Interpretation:
The information required to interpret the drug
concentration include:
Time at which blood sample taken
Time at which dose is given
Dosage regimen (Dose, Duration, Dosage Form)
Patient demographic (sex, age, concomitant
disease, ethnicity, etc)
Co medications
Indications for monitoring
PK and therapeutic range of the drug

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

24. FACTORS AFFECTING SDC
1. Disease states: renal, liver, cardiac
2. Habits: diet, smoking, drinking
3. Pregnancy, age, weight
4. Non-compliance
5. Electrolyte balance : Digoxin vs K+ & Ca++
6. Drug interactions
7. Plasma protein binding
8. Bioavailability
9. Sampling time

25. COMMONLY MONITORED DRUGS
 Bronchodilators: Theophylline
 Antibiotics : Aminoglycosides - Gentamicin,
Amikacin
 Others - Vancomycin
 Immunosuppressants: Cyclosporine
 Anticancers: Methotrexate

26. COMMONLY MONITORED DRUGS
Antiepileptics: Phenobarbital,
Phenytoin,Carbamazepine, Valproate
 Cardiac Drugs : Digoxin*,
Procainamide, Lidocaine
 Psychoactive Drugs: Lithium,
TCA
 Analgesics: Aspirin, Paracetamol

27. PROBLEMS OF TDM SERVICE
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 other
necessary data
No consultation when problems arise

28. DETERMINATION OF RATE CONSTANT
:

31. PLOTS OF DRUG DISTRIBUTION
d
r

33. Scatchard plot

34. N

35. Klotz plot

37. Hitchcock plot

38. References:-
Biopharmaceutics and pharmacokinetics,
D.M.BRAHMANKAR pg no 134-136.
Best practice in therapeutic drug monitoring
Annette S. Gross Department of Clinical Pharmacology,
Royal North Shore Hospital, St Leonards NSW 2065,
Australia.
THE THERAPEUTIC DRUG MONITORING AS A BASIS
FOR INDIVIDUALIZING PATIENT DOSAGE REGIMEN,
Journal of Health Sciences Management and Public
Health, Jozef Novotný, Tomáš Èech1