Concept of narrow therapeutics drugs, understanding therapeutic drug monitoring definitions, indications

1. THERAPEUTIC
DRUG MONITORING
Dr. Ramesh Bhandari
Asst. Professor
Department of Pharmacy Practice,
KLE College of Pharmacy, Belagavi

2. PRELIMINARY CONCEPTS
FOR TDM

3. PHARMACOKINETIC HOMOGENEITY
Changes in the plasma drug
concentration reflect Proportional
changes in the drug concentration in
other tissues.

4. Drug in Tissue
Drug in Blood
Sample removed for drug concentration
determination

5. Time
Plasma
Concentration
Maximum tolerable concentration
Minimum effective concentration
C
max
Tmax
Duration of
action
Onset
of
action
Termination
of
action
PLASMA VS TIME PROFILE OF ORALLY ADMINISTERED DRUG

6. •Therapeutic range is the plasma concentration
range that is effective and safe in treating
specific diseases.
•Therapeutic Index is a ratio between minimum
effective concentrations to the maximum
tolerable concentration.
THERAPEUTIC WINDOW/RANGE

7. NARROW THERAPEUTIC INDEX DRUGS
•Therapeutic index of the drug is ≤ 3
•Higher inter-individual variability (CV > 20%)

8. MONITORING OF DRUG THERAPY
1. Pharmacokinetic Measures using TDM
2. Pharmacodynamics Measures using Surrogate Markers
3. Therapeutic Outcomes using Clinical End Points

9. PHARMACOKINETIC MEASURES
It includes measurement of drug concentrations in the blood
or plasma i.e. by Therapeutic Drug Monitoring (TDM).
Is the drug getting
to the site of
action ?

10. PHARMACODYNAMICS MEASURES
For many drugs there are no readily available measure of effect or it is
insufficiently sensitive.
Clinician routinely monitor drug pharmacodynamics by directly
measuring physiological indices (Surrogate Markers) of therapeutic
response.
Is it producing
required
pharmacological
effect ?

11. Surrogate Marker is defined as an endpoint that is measured
in place of true end point and that relates in someway to
the primary end point.
Surrogate markers are cheaper and easier to measure than
true end point and can be measured quickly.
Eg: Clotting time in patient on warfarin anticoagulation
therapy, Glucose level in diabetic patient using insulin
products, etc.

12. THERAPEUTIC OUTCOMES
Monitoring therapeutic outcomes in patient/individual:
Reduced frequency of asthma attacks – Bronchodilators
Decreased frequency of seizure – Anti-epileptic drugs
Reduced swelling - Diuretics

13. Prescribed Dosing
Regimen
Drug at Site of
Action
Drug Effects
Pharmacokinetic Variability
a) Compliance
b) Dosing or medication Error
c) Tissue and body fluid mass and
volume
d) Drug interactions
e) Elimination
Pharmacodynamic Variability
a) Drug receptor status
b) Genetic factors
c) Drug interactions
d) Tolerance
PHARMACOKINETICS PHARMACODYNAMIC

14. THERAPEUTIC DRUG
MONITORING

15. INTRODUCTION
•Therapeutic drug monitoring is the individualization
of drug dosage by maintaining plasma or blood
drug concentrations within a targeted therapeutic
range or window.
•Commonly known as TDM
•It involves measuring serum drug concentration at
designated intervals to maintain constant
concentration in a patient bloodstream.

16. •TDM Aims to promote optimum drug therapy
by maintaining serum drug concentration within
a therapeutic Range/Window.
•Therapeutic monitoring of plasma drug
concentrations is valuable only if a relationship
exists between the plasma drug concentration
and the desired clinical effect or between the
plasma drug concentration and an adverse
effect.

17. •Therapeutic drug monitoring blends knowledge
of therapeutics, pharmacology, pharmacokinetics,
laboratory technology and clinical medicine and
applies it to certain drugs that require
determination of patient specific dosage
regimens to maximize therapeutic
effectiveness while minimizing toxicity.

18. TDM WILL BE USEFUL IN FOLLOWINGS:
1) Narrow therapeutic indexed drugs
2) Direct relationship exists between the drug or drug
metabolite levels in plasma and the pharmacological or
toxic effects.
3) Therapeutic effect can’t assessed by the clinical
observation.
4) Large individual variability in steady state plasma
concentration exists at any dose.
5) Appropriate analytical techniques are available to determine
the drug and metabolite levels

19. TDM IS NOT USEFUL IF
Clinical outcome is unrelated either to dose or to
plasma concentration.
Dosage need not be individualized
Pharmacological effect can be clinically quantified
Concentration effect relationship remains
unestablished
Drugs having wide therapeutic range such as
calcium channel blockers or beta blockers

20. TDM PROCESS
1. Reasons for Requesting TDM
2. The Biological Sample
3. The Request
4. Laboratory Measurement
5. Communication of the Results by Laboratory
6. Clinical Interpretation
7. Therapeutic Management

21. 1. Reasons for Requesting TDM
Narrow Therapeutic Index
Therapeutic failure
Poorly defined End point
Non compliance
Wide variation in the metabolism of the drugs
Prevention of Adverse drug effects
Toxicity suspected
Assess therapy
Potential drug interaction due to change in co-medication

22. 2. The Biological Sample
It is important that biological sample collected should provide
a clinically meaningful measurement.
Blood sample should be collected once the drug concentration
have reached steady state (at least 5 half lives at the current
dosage regimen)
Steady state may be reached earlier if a loading dose has been
administered (drugs with long half lives).
However, drugs with long half lives should be monitored
before steady state to ensure that individuals with impaired
metabolism or renal excretion are not in the risk of developing
toxicity.

23. If toxicity suspected – concentration should be
measured as soon as possible.
Absorption is variable after oral dosing so blood
sample should be collected in elimination phase rather
than absorption/distribution phases.
Generally blood samples are collected at the end of
the dosage interval i.e. trough concentration.
For antibiotics given intravenously, peak
concentrations are also measured.

24. •Usually drug concentration are monitored in venous
blood, serum or plasma.
•In general serum or plasma concentration are
comparable.
•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.
•Utility of saliva measurements and other biological
fluids are not routinely sampled.

25. 3. The Request
 Patient demographics such as age, disease state,
ethnicity etc. are critically important to know the
variation in Pharmacokinetic and pharmacodynamics.
So these details should 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 important for
requesting clinicians to clearly communicate the
expectation of a high concentration and need for a
rapid feedback of results.

26. 4. Laboratory Measurement
Drug assay must be performed within a clinically
useful timeframe.
The assay procedure should be validated.(accuracy,
precision, sensitivity, specificity, limit detection)
If possible the assay procedure should be evaluated
with an external quality assurance program.
Senior laboratory staff should verify the assay results.

27. Commercial kits can be used wherever possible and
found economical. However, kits are not available for
all the drugs.
The analytical methodology used should ideally:
• Detect small amount of drugs.
• Differentiate between compounds of similar
structure, unchanged drug and metabolite.
• Simple enough to use as routinely.

28. Various analytical techniques available for TDM are:
•Thin Layer Chromatography
•Mass Spectrophotometry
•HPLC and HPTLC
•GC
•Radio Immuno assay
•Enzyme Immuno assay
•Least Count Mass Spectrometry

29. 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.
To relate concentration back to dose, mass units are
preferable.

30. The result should clearly state the therapeutic
concentration range for the drug assayed.
It must be understood that different indications for
therapy, age or ethnic differences in PK and PD could
results in different therapeutic ranges being
appropriate for different population groups.
Therefore, critical assessment of the original
literatures and consensus recommendations for
therapeutic ranges should be encouraged.

31. 6. Clinical Interpretation
Clinical interpretation can add value and convert
therapeutic measurement service into therapeutic drug
monitoring service.
The information required to interpret the drug
concentration include:
o Time of blood sampling
o Time at which dose is given
o Dosage regimen (Dose, Duration, Dosage form)
o Patient demographics (age, gender, concomitant
diseases)
o Indication for monitoring
o PK and therapeutic range of the drug

32. Serum concentration lower than anticipated
Patient non compliance
Error in dosage regimen
Wrong drug product
Poor bioavailability
Rapid elimination
Increased plasma protein binding
Enlarge apparent volume of distribution
Timing of blood sample
Steady state not reached

33. Serum concentration higher than anticipated
Patient compliance
Error in dosage regimen
Increased bioavailability
Decreased elimination
Decreased plasma protein binding
Drug interaction due to inhibition of elimination
Smaller apparent volume of distribution

34. Serum concentration within range but patient
does not respond to therapy
Altered Receptor Sensitivity (Intolerance)
Drug interaction at Receptor site

35. 7. Therapeutic Management
The Clinician will modify a drug dosage regimen
with respect to information available.
Dose Adjustment:
For drugs with linear kinetics:
New Dose = 𝑜𝑙𝑑 𝑑𝑜𝑠𝑒 𝑥
𝐷𝑒𝑠𝑖𝑟𝑒𝑑 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
old drug concentration

36. Limitations of TDM Process
1) Scientific accuracy of the drug assays
2) Laboratory variability in reporting
3) Validity of suggested target ranges
4) Lack of training and skills
5) Cost involved
6) Limited infrastructure facilities

37. STUDY PROTOCOL FOR TDM
1) Title of the study / project
2) Investigators:
1. Chief investigator
2. Joint investigator
3. Co- investigator a) Clinical
b) Research fellow
3) Place of study
4) Patient recruitment place
5) Need for TDM study
6) Objective for study
7) Criteria for selection of patients
8) Patient History
9) Withdrawal of blood sample and storage
10) Instrument for
a) Measurement of drug levels
b) Measurement of clinical parameters
(ECG, EEG, Respiration etc.)
11) Report preparation
12) Clinical interpretation 37