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Therapeutic Drug

Monitoring

Sandeep.B,
M.Pharm, II Semester,
Department of Pharmacy Practice

Contents:

Introduction

Necessity of TDM

Objectives

Criteria for TDM

Drugs requiring TDM

Sampling

Examples

Factors influencing plasma drug concentration

Analytical techniques used in TDM

Clinical interpretation of results

Role of Pharmacist in TDM

Limitations

References

Introduction:

Therapeutic drug monitoring is defined as a a


process of assessing concentration of the drug in
biological fluids such that it is maintained within the
therapeutic range.

It aims at individualizing the dose for a patient to


obtain maximum benefit.

TDM closely observes the changes in the signs and


symptoms of patient and the related laboratory data
as well which affect the clinical outcome of the
therapy.

TDM establishes safety and effectiveness of therapy.

Plasma drug concentration

Plasma drug Concentration Vs Time


Plot
Toxic Level
MSC

Therapeuti
c Range

MEC
Subtherapeut
ic Level

Time

Necessity for TDM:

TDM is necessary for certain drugs having narrow


therapeutic range or non-linear pharmacokinetics,
where the dosage individualization becomes difficult.

It is useful in assessing the variability between the


individual patients response to drug therapy which
arises due to differences between:

Dose of the drug and its plasma concentration


(Pharmacokinetic variability)

Concentration of the drug at the receptor site and its


response (Pharmacodynamic variability)

Objectives:
1.

Obtaining maximum beneficial outcome of drug therapy by


approximate dosing of drugs.

2.

Attaining the required therapeutic concentration of the drug


within least time and maintaining the concentration within the
therapeutic range.

3.

Providing medical advantage by reducing the chances of drug


toxicity.

4.

Providing economic convenience to the patients by shortening


their hospital stay.

5.

Monitoring of factors like disease state, patients characteristics,


drug interactions etc., in order to reduce patient variability.

6.

Dosage adjustment in patients with pre-existing hepatic or renal


impairment and thus preventing drug accumulation in the body.

7.

TDM can provide an effective means of individualization of dosing


of some drugs that have unpredictable dose-response
relationship.

Criteria for TDM:


The criteria for obtaining a valid TDM which is
clinically effective is:
1.

A well established correlation among concentration of


drug in plasma and its therapeutic response and toxicity.

2.

Meagre correlation between concentration of drug in


plasma and its dose.

3.

An acceptable evidence for performing TDM i.e., no


response of the patient to the drug therapy, patients
non-compliance, signs and symptoms of toxicity.

4.

Availability of specific and well established methodology.

5.

Collection of biological samples at regular intervals.

6.

There should be sufficient clinical data which permits


rapid and accurate interpretation of clinical outcome.

Drugs requiring TDM:


The following features of the drugs necessitate
their TDM:
1.

Narrow therapeutic range

2.

Significant pharmacokinetic variability (ADME)

3.

Drugs which show therapeutic as well as ADR based


on their relative concentrations

4.

Availability of cost effective drug assay

5.

Drugs which follow saturation metabolism

1.

Anticancer drugs- Paclitaxel, Cisplatin,


Methotrexate

2.

Antiepileptics- Phenytoin, Fosphenytoin, Valproic


acid,

3.
4.
5.
6.

Carbamazepin

Cardiotonics- Digoxin
Immunosupressants- Cyclosporin, Tacrolimus
Antibiotics- Ampicilline, Vancomycin
Antiarrythmics- Amiadarone, Lidocaine

Sampling:

Proper selection of Sample time is of vital importance


in obtaining an effective TDM.

Generally biological samples (mostly venous blood)


are collected after the drug reaches steady state
concentration.

For most of the drugs, Steady-state concentration is


reached at least after 5 biological half lives.

The point in dosing interval which is least inconsistent


is known as pre-dose or trough concentration.

The dosing interval and duration of dosing are the


factors which influence variations in drug
concentrations in plasma.

Drug

Therapeutic
range

Half-life in
Adults

Average time
taken to reach
steady state
concentration

Digoxin

0.5-2 mcg/l

30-50 hrs

7-12 days

Phenytoin

10-20 mg/l

10-30 hrs

8-21 days

Carbamazepine

5-12 mg/l

l0-30 hrs

3-5 days

Lithium

0.5-1 mmol/l

14-30 hrs

5-8 days

Amiodarone

1-2.5 mg/l

27-105 days

3-6 months

Cyclosporin

100-200 mcg/l

19 hrs

3-4 days

Theophylline

7-15 mg/l

Smokers (7-11
hrs)
Nonsmokers (3-5
hrs)

24-36 hrs

Gentamycin

<0.5 mg/l

2-5 hrs

<24 hrs

Vancomycin

5-15 mg/l

3-8 hrs

24-48 hrs

Factors influencing plasma drug


concentration:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Patient characteristics
Patient compliance
Dosage regimen and Duration of therapy
Time of sampling
Alteration in Protein binding
Alteration in elimination of drugs
Pathological characteristics
Drug interactions
Smoking and alcohol consumption
Sampling and Laboratory errors

Analytical techniques used in TDM:


The techniques chiefly employed for detection of
drugs in a TDM laboratory are:
1. HPLC
2. GC/MS
3. LC/MS
4. RIA
5. PETINIA
6. EIA
7. EMIT
8. FPIA
9. CEDIA
10. Chemiluminiscence
11. One-step Dry Chemistry Technique

Clinical interpretation of results


Clinical conditions requiring TDM for drugs used for
prophylaxis
Collection of biological
sample
Transfer to laboratory and estimation of drug concentration by
suitable method
Interpretation of TDM results with reference to clinical
conditions
Inadequate/Lack of Clinical
response
Below TR
Check the
follow up
of
therapy
Increase
dose if
required

Within
TR

Check
the
follow up
of
therapy
If required

Above
TR

Change or
re consider
drug
therapy

a small
change in dose should
be considered

Satisfactory Clinical
response
Below
TR

Other
possible
reasons for
signs of
toxicity
should be
considered.
Laboratory
errors should

Within
TR

Other possible
reasons for
signs of
toxicity should
be considered.
Lower dose
can be given if
result
indicates the

Above
TR

Discontin
ue the
therapy
and
restart
with a low
dose

Role of Pharmacist in TDM:

A clinical pharmacist may assist other health care


professionals by advising them about correct use if TDMsampling time, sampling technique and interpretation of
results.
They also may be engaged in:

1.

Selecting initial drug dosage regimen-dose, dosing interval,


route of administration, dosage form.

2.

Depending upon the TDM results and patients response,


revision and adjustment of dosage regimen should be done.

3.

Assessing various other reasons for unexpected results like


patients non-compliance, medication or laboratory errors,
DDIs etc.

4.

Evaluating and adjusting dosage for patients on


haemodialysis.

5.

Managing acute drug interactions.

Limitations of TDM:

Scientific accuracy of drug assays

Laboratory variability in reporting

Validity of suggested target ranges.

Active metabolites which contribute to the


therapeutic response cannot be measured.

References
1.

Birkett DJ. Therapeutic drug monitoring. Aust Prescr


1997;20:9-11

2.

Therapeutic Drug Monitoring (TDM), An Educational Guide.


www.siemens.com/diagnostics

3.

Summers, K. K., T. C. Hardin, S. J. Gore, and J. R. Graybill. 1997.


Therapeutic drug monitoring of systemic antifungal therapy. J.
Antimicrob. Chemother. 40:753-764.

4.

Schumacher GE. Clinical pharmacokinetics and therapeutic


drug monitoring. Comprehensive pharmacy review; 7:732-741

5.

Flexner D. Update on HIV pharmacology and therapeutic drug


monitoring. Perspectives - Pharmacology and therapeutic drug
monitoring Vol 9 Issue 3 July 2001

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