2. DEFINITION
Therapeutic drug monitoring (TDM) is generally
defined as the clinical laboratory measurement of
a chemical parameter that, with appropriate
medical interpretation, will directly influence drug
prescribing procedures 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.
The goal of this process is to individualize
therapeutic regimens for optimal patient benefit.
2
3. CRITERIA IN WHICH TDM IS
USEFULL
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.
3
4. 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.
4) when concentration effect relationship remains
unestablished.
5) drugs with wide therapeutic range such as beta
blockers and calcium channel blockers.
4
5. INDICATIONS FOR TDM
Drug efficacy difficult to establish clinically
(Phenytoin).
Suspected toxicity
Inadequate therapeutic response
Compliance concerns
Dosage change
Change in patient’s clinical state
Change in co-medications
Manifestations of toxicity and disease state are
similar
5
6. INTERPRETIVE CRITERIA
Measuring the blood concentration of certain
therapeutic drugs is only one aspect of effective
TDM monitoring.
True TDM testing takes into consideration all the
factors that can affect results, as well as all the
factors that can affect interpretation, as described
below:
APPLICABILITY OF TR:
Therapeutic ranges are recommendations
derived by observing the clinical reactions of a
small group of patients taking the drug.
6
7. CONT…
The lower limit(trough) is set to provide ~50% of
the maximum therapeutic effect, while the upper
limit (peak) is defined by toxicity, not therapeutic
effect.
FACTROS THAT AFFECT RESULT:
Pharmacokinetics
Pharmacodynamics
Dose
Sampling time and type
Testing methodology
7
8. CONT…
PHARMACOKINETICS:
Pharmacokinetic variability describes the relationship
between the dose administered and the resulting
plasma concentration.
Major Sources of Pharmacokinetic Variability
Patient Compliance – lack of
Age – neonates, children, elderly
Physiology – gender, pregnancy
Disease – hepatic, renal, cardiovascular, respiratory
Drug-to-drug interactions
Environmental influences
8
9. CONT…
PHARMACODYNAMIC:
Pharmacodynamic variability describes the way in
which the drug affects the body’s functions, and
the relationship between the drug’s chemical
structure, actions, and effects.
FACTORS THAT AFFECT INTERPRETATION:
Protein binding
Active metabolites
9
10. Cont….
OTHER CONSIDERATIONS:
Steady state
Turnaround time
Sample Information Required for Accurate
Interpretation:
Time of sample in relation to last dose
Duration of treatment with the current dose
Dosing schedule
Age, gender
Other drug therapy
Relevant disease states
Reason for request.
10
11. COMMONLY MONITORED DRUGS
There are several classes of drugs commonly
monitored to ensure correct blood concentration,
including the following:
Antiepileptics
Antiarrythmics
Antibiotics
Antineoplastics
Antimanics
Bronchodilators
Immunosuppressives
11
12. ANTIEPILEPTICS
This class of drugs, also known as
anticonvulsants, is most often prescribed for the
management of epilepsy, though it may also be
prescribed for other indications such as tic
douloureux, myotonia, bipolar effective disorder,
prophylaxis of certain varieties of migraine and of
cardiac dysrhythmia.
12
13. CONT…
PHENYTOIN:
Indication:Corrects tonic- clonic seizures. Often
used instead of phenobarbital.
Therapeutic range:10 – 20 μg/ mL
Toxicity: manifests as nystagmus, ataxia and
confusion.
13
15. Cont…
Test methods: These drugs are most commonly
tested with serum or plasma using any of the
several commercially available immunoassays.
A more sensitive and specific alternative is HPLC.
However due to high cost and long time to result,
it is not used routinely.
15
16. Cont..
Test timing: Trough concentrations are most often
obtained for monitoring purposes because they
provide the most consistent concentration values
from dose to dose. Peak concentration testing is
not recommended.
Therapeutic range:Therapeutic ranges for
antiepileptic drugs should be used to help
determine the optimal therapeutic concentration
for an individual patient,as one patient’s optimal
therapeutic concentration may fall into the toxic
range, while another’s may fall below the
established therapeutic range.
16
17. Cont..
Application of Therapeutic Ranges for
Antiepileptic Therapies:
Guide treatment before the clinical response has
had time to become clear
Determine cause of treatment failure
Aid in the diagnosis of symptoms that may
represent drug over-dosage
17
18. Cont…
Antiepileptic Drug Monitoring Indications:
Soon after steady-state conditions are initially
expected
When the patient is seizure-free and experiencing
no adverse effects (determines therapeutic
concentration).
When questioning an over-dose.
To determine the cause of relapse
Before and after any change in dose
Before and after introducing a drug that may
interact.
18
19. ANTIARRHYTHMIC DRUGS
DIGOXIN:
Indication:Used to improve cardiac contraction in
congestive heart failure and to correct
supraventricular tachycardia.
Therapeutic range:0.9 – 2 ng / mL
Toxicity:may be nonspecific eg nausea, vomiting,
abdo pain & confusion but remember bradycardia
with increasing of heart block especially with AV
junctional escape rhythms and visual disturbance
(xanthochromia).
19
20. Cont..
PK PROBLEMS:10% population have enteric
bacterium (E. lentum) that can metabolize
digoxin. Large volume of distribution (≈ 5L/kg lean
BW) and predomin excreted unchanged in the
urine with CL∝ GFR.
Test methods: Digoxin is the most commonly
monitored therapeutic drug.
ADVIA Centaur and EMIT assays from Siemens
are proven.
20
21. Cont..
Large of number of interactions -
MECHANISM CONDITIONS/
DRUGS
PK ↑ Vd and CL
↓ Vd and/or CL
↑ absorption
↓ absorption
↓ GFR
Thyrotoxicosis/T4
Verapamil, amiodarone,
propafenone
Erythromycin, omeprazole
Exchange resins, kaolin
Any cause of renal
impairment/Cyclosporine
PD increase block
of the Na pump
Hypokalaemia / Kaluretic
diuretics
21
22. Cont….
Test timing: For all antiarrhythmic drugs, samples
should be collected at least 6 hours(preferably 8)
post dose to allow for absorption and distribution.
Therapeutic range:
For patients with normal renal function, who have
achieved steady-state levels, the therapeutic
range for digoxin is based on blood samples
obtained 8 hours after the last dose.
Testing of earlier samples may produce falsely
elevated results.
Numerous factors affect the action of these drugs.
22
23. AMINOGLYCOSIDES
Monitoring is mandatory in ALL patients.
AG accumulate in the renal cortex to levels 100-
fold > plasma >95% of AG are cleared by
glomerular filtration.
Toxicity:
NEPHROTOXICITY (Proximal tubule)
OTOTOXICITY cochlear (hearing
-deficits):amikacin
gentamycin
vestibular(disturbed blnc)
gentamycin
23
24. AMINOGLYCO
SIDES
INDICATION THERAPUTIC
RANGE
AMIKACIN Used to treat different types
of bacterial infections.
Most often used to treat
severe infections with
multidrug resistant gram-
negative bacteria
Peak:15 – 30 μg/mL
Trough:1 – 10 μg/mL
GENTAMYCIN Given to patients with
potentially life-threatening
bacterial infections. Excess
dosage can cause kidney
and auditory nerve damage
Peak: 5 – 10 μg/mL
Trough: 1 – 2 μg/mL
NETIMICIN Used to treat serious
infections, particularly those
resistant to gentamycin
Peak: 1 – 12 μg/mL
TOBRAMYCIN tobramycin is more active
against
Pseudomonas aeruginosa
Peak: 5 – 10 μg/mL
Trough: 0.5 – 2 μg/mL
24
25. CONT..
TEST METHODS:HPLC can also be used for
many of these drugs, with the exception of
Gentamicin,which is not a single substance.
TEST TIMING: aminoglycoside therapy strives to
achieve a high peak, followed by a low trough to
avoid accumulation.
Under traditional dosing regimens, this requires
monitoring of both peak(~0.5 hours after
transfusion) and trough (within 0.5 hours of the
next dose) concentrations, which may be
frequently repeated until results stabilize.
25
27. CLINICAL SIGNIFICANCE
27
TDM data provides the clinician with greater
insight into the factors determining the patients
response to drug therapy.
For example when a patient fails to respond to a
usual therapeutic dose,measurement of plasma
level can help to distinguish a noncompliant
patient and a patient who is a true non-responder.
TDM also provides useful information regarding
individual variations in drug utilization patterns
and alteration in drug utilization as a
consequence of altered physiological state or
disease process.
28. CONT…
28
TDM is a useful adjunct in treating many patients
provided the potential pit falls and problems are
considered.
Therapeutic Drug Monitoring and pharmacokinetic
studies help the physician provide optimum care by:
Helping the physician initiate therapy to achieve the
maximum therapeutic effect for the patient in the
shortest amount of time.
Minimizing the risk of drug toxicity.
Ensuring drug side effects are controlled and
minimized.
29. REFERENCE
1. Shenfield GM.Therapeutic Drug Monitoring beyond
2000.Br. J Clin. Pharmacol, 2001; 52: 3S-4S.
2. Gross AS.Best practice in Therapeutic Drug
Monitoring. Br. J Clin. Pharmacol, 2001; 52: 5S-10S.
3. Nicoll D.Pocket Guide to Diagnostic Tests, Third
Edition. Lange/McGraw-Hill, 2001.
4. Birkett DJ.Therapeutic Drug Monitoring.Aust
Prescr, 1997; 20:9-10.
5. Eadie MJ.Therapeutic Drug Monitoring –
Antiepileptic Drugs.Br. J Clin. Pharmacol, 2001; 52:
11S-20S.
29
30. CONT…
6. Campbell TJ, Williams KM.Therapeutic Drug
Monitoring: Antiarrhythmic Drugs.Br. J Clin.
Pharmacol, 2001; 52: 21S-34S.
7. Begg EJ, Barclay ML, and Kirkpatrick MJ.The
Therapeutic Monitoring of Antimicrobial
Agents.Br. J Clin. Pharmacol, 2001; 52: 35S-43S.
8. Kricka, L. and Wild, D.Signal Generation and
Detection Systems.The Immunoassay Handbook.
Second Edition. (Ed: David Wild), 165 (Nature
Publishing Group, NY,NY 2001).
30