1. THERAPEUTIC DRUG MONITORING
(TDM)

2. TDM refers to the individualization of dosage by
maintaining plasma or blood drug concentration
within a target range (therapeutic range).
Goal of TDM is to achieve a desired beneficial
effect with minimal adverse effects.
WHAT IS TDM ?

4. Therapeutic Index
• High therapeutic index
– NSAIDs
• Aspirin
• Tylenol
• Ibuprofen
– Sedative/hypnotics
• Benzodiazepines
– Most antibiotics
– Beta-blockers
• Low therapeutic index
– Lithium
– Neuroleptics
• Phenytoin
• Phenobarbital
– Some antibiotics
• Gent/Vanco/Amikacin
– Digoxin
– Immunosuppressives

5. Therapeutic Index
Plasma drug concentration
ToxicTherapeutic range
Toxicity
Sub-therapeutic

6. Why monitor plasma drug
concentrations?
• Avert toxicity
• Optimize dose/therapeutic response
• Detect changes in pharmacokinetics
• Monitor compliance

7. WHY TDM ?
1. Each person will have ADME at different
rates based on their
a) age,weight, gender,
b) genetic makeup,
c) diseased conditions.
2. Useful in maintaining drug concentration
within the therapeutic range which are taken
for lifetime, and reduces toxic effects.

8. WHY TDM ?
3. Identify patient noncompliance, decrease in
the efficiency of and dysfunctions in the body
metabolism and elimination of drug.
4. Identify drug interactions.
5. Prescribe the exact dose thereby min the toxic
effects.

9. Purpose of TDM
• To confirm ‘effective’ concentrations
• To investigate unexpected lack of efficacy
• To check compliance
• To avoid or anticipate toxic concentrations
• Before increasing to unusually large doses
• Limited role in toxicology - drug screen

10. DOES ALL DRUGS REQURE TDM?
TDM is useful if:
Drug have narrow therapeutic range,
Therapeutic effect cannot be readily assessed
By the clinical observation,
Large individual variability in plasma conc.
A direct relationship exists between the drug or
drug metabolite levels in plasma and the
pharmacological or toxic effects.
Drug follow non-linear kinetics.

11. TDM is unnecessary when:
Drugs with wide therapeutic range.
Pharmacological effects can be clinically
quantified,
Drug follow linear kinetics,
Clinical outcome is unrelated to either dose or
plasma conc.
DOES ALL DRUGS REQURE TDM?

12. Major indications for TDM can be summarized as:-
1.Low therapeutic index,
2.Poorly defined clinical end point,
3.Therapeutic failure,
4.Drugs with saturable metabolism,
5.Wide variation in the metabolism of drug,
6.Major organ failure,
7.Prevention of adverse effects of life time drugs.

14. Therapeutic range for commonly monitored drugs
Amicacin 20-30ug/ml
Cabamazepine 4-12 ug/ml
Digoxin 0.5-2.1 ug/ml
Gentamicin 5-10 ug/ml
Phenytoin 10-20 ug/ml
Procainamide 4-10 ug/ml
Quinidine 1-4 ug/ml
Theophylline 10-20 ug/ml

15. TDM OF ESTABLISHED DRUGS:-
1. Cardio active drugs : amiodarone, digoxin,
digitoxin
disopyramide,
lignocaine,
procainamide,
propranolol and
quinidine
2. Antibiotics : gentamycin, amikacin
and tobramycin
3. Antidepressants : lithium and tricyclic antidepressants
4. Antiepileptic drugs : Phenytoin,
phenobarbitone
benzodiazepines,
carbamazepine,
Valproic acid and
ethosuximide
5. Bronchodilators : theophylline
6. Cancer chemotherapy : methotrexate
7. Immunosuppressives : cyclosporine

16. Criteria for TDM

18. Factors influencing drug variability
• Variation in drug absorption
• Presence of other drugs
• Drug interactions
• Genetic difference
• Diseases states
• Physiologic differences

19. Process of TDM
• Development of plasma profile in each patient
1)administering a predetermined dose of drug
2)Collection of blood samples
3)Determination of blood samples in each sample
4)plasma profile and pharmacokinetic model
development
• Clinical effect of drug
• Development of dosage regimen
• Diagnosis, dosage form selection, dosage regimen
,initiation of therapy and evaluation of clinical response

21. Pharmacokinetic Considerations
• Is the aim to provide constant concentrations? - eg
anticonvulsants
• Is the aim to achieve transient high concentrations
without toxicity? - eg gentamicin
• Are drug concentrations likely to vary greatly
between individuals on the same dose? - eg
phenytoin
• Remember it takes around 5 half-lives to reach
steady state

22. Practical considerations
• Can the lab actually measure the drug?
• What sample is needed?
• What is the right timing?
• Is there an accepted ‘therapeutic range’
– MEC - threshold concentration above which efficacy is
expected in most patients with the disorder
– MTC - upper concentration above which the rate and
severity of adverse effects become unacceptable

23. HOW DOES TDM WORK?
The drug dosage to reach the therapeutic level
must be determined on ADME of drug, age,
weight, gender.
The doctor adjusts the dose upwards and tests
blood conc frequently until the appropriate
steady state level is reached.
If patient levels are too high, the doctor will
adjust them lower, and vice versa.

24. Samples?
plasma or serum is used for drug assays
whole blood:- cyclosporin, tacrolimus, sirolimus there are
large shifts of drug between red cells and plasma with storage
and temperature change so whole blood is assayed
saliva, which gives a measure of the unbound drug
concentration, may be a useful alternative when blood
samples are difficult to collect.
phenytoin ,Lithium, amitryptyline

25. TIMING OF SAMPLE COLLECTION
Peak conc
Trough
Conc
Time (hours)
Conc(ug/l)

26. TIMING OF SAMPLE COLLECTION
The timing of blood collection is an important
part of therapeutic drug monitoring.
Through experience and studies, doctors know
when to expect peaks and troughs to occur and
will request blood sample collections as either
trough levels(usually drawn just before the next
dose), peak levels(timing varies depend on the
drug), or sometimes will request random level.

27. TIMING OF SAMPLE COLLECTION
Trough conc are commonly used for anti-convulsant
drugs,
peak conc may be useful for some antibiotics.
AUC:- For some immunosuppresants and anticancer
drugs.
drugs with long half-lives such as phenobarbitone and
amiodarone, samples can be collected at any point in the
dosage interval.
Correct sample timing should also take into account
absorption and distribution, eg digoxin, so samples are
collected after 6 hours of administration.

28. ANALYTICAL METHODOLOGY:-
The analytical methodology employed should ideally:
1.Distinguish between drug and its metabolites,
2.Detect small amounts,
3.Specificity
4.Unaffected by other drugs administered,and
5.Should be accurate, precise, linearity.

29. ANALYTICAL METHODOLOGY
Commonly used analytical methods are:
1.Spectrophotometry and fluorimetry,
2.Thin layer chromatography,
3.HPLC and GLC,
4.Radio immuno assay(RIA)
5.Enzyme immuno assay(EIA)
6.Fluorescence ploarization immunoassy(FPIA)

30. For therapeutic drug monitoring the information required to
allow interpretation of the result should include:-
1. the time of the sample collection,
2. the time of the last dose,
3. the dosage regimen and
4. the indication for drug monitoring.

31. Sample timing for some important drugs:
a)Phenytoin: Since phenytoin has a long half life a single daily
dose may be employed and so the timing of concentration
monitoring is not critical.
b) Carbamazepine: Its half life may be as long as 48 h following a
single dose. A through concentration taken just after a dose
together with a peak level three hours later is ideal.
c) Digoxin: The measurement must be made atleast six hours after
a dose to avoid inappropriate high levels.
d) Theophylline: This drug has a narrow therapeutic index and
timing of sampling is not critical if the patient is receiving one of
the slow release formulations.
e) Lithium: A 12 hr sample gives the most precise
guide to dosage adjustment.

32. The drug concentration in the collected samples
are measured, and the other data such as high
serum creatinine and high blood urea nitrogen
levels are also measured to check the kidney
function.

33. Sample concentrations lower than anticipated
Patient non compliance
Error in dosage regimen,
Rapid elimination,
Timing of sample
changing hepatic blood flow
Poor bioavailability.
Reduced plasma binding.

34. Sample concentrations higher than anticipated
Error in dosage regimen
Rapid bioavailability,
Slow elimination,
Increased plasma protein binding
Decreased renal/hepatic function

35. Serum concentration correct but patient does not
respond to therapy
Altered receptor sensitivity(tolerance)
Drug interaction at receptor site

36. Pharmacokinetic software are available for dose
calculation of drug with narrow therapeutic window
DATAKINETICS
ABBOTTBASE PHARMACOKINETIC SYSTEM
The dosage regimen is calculated by using the
NOMOGRAM by considering the age, body weight, and
physiological state of the patient.

39. Therapeutic Drug Monitoring

40. Therapeutic Drug Monitoring
• Relates concentrations of drug in blood to response
• Blood concentrations surrogate for the concentration at
the site of action
• Has been established on the principle that the
concentration correlates better than the dose with the
drug effect
• Is important when
– the dose cannot be titrated against response eg INR,
cholesterol
– the drug is being used to prevent infrequent occurrences - eg
epilepsy

41. First Principle of TDM
• “Knowledge of serum concentrations is most
helpful when the drug in question requires
individualized dosing for optimal efficacy and
more routine measures of therapeutic success
are unavailable.”

42. Conditions that must be met
• Blood concentrations can be accurately reliably and
economically measured
• There is sufficient inter-individual variation in drug
handling to warrant individualisation of dose
• There is a clear relationship between concentration
and beneficial and/or adverse effects, particularly if
there is a narrow therapeutic index
• The effects are due to the parent drug and not its
metabolites

43. Methodological Difficulties in
establishing ‘Therapeutic Range’
• Good data relating concentration to effect are
seldom available
• Ideally it would require trials where
participants were randomised to different
plasma concentrations with follow-up and
accurate and unbiased measurement of the
outcomes
• See diagram of therapeutic range

44. TDM - examples
• Lithium - used for bipolar disorder
• Toxic - neurological, cardiac, renal
• Narrow therapeutic range:
– 0.8 - 1.2 mmol/L acutely
– 0.5 - 0.75 mmol/L for maintenance
– Chronic concentrations of 3.0 are potentially lethal
• Renal clearance of Li can be affected by
diuretics and NSAIDs

45. Anticonvulsants
• Variable dose dependant kinetics
• Most metabolised through cytochrome P450 system
• Concentration-related CNS toxicity can be partly
avoided by TDM
• However severe skin rashes, liver and marrow toxicity
cannot be predicted or avoided
• With phenytoin small dose increases can produce
disproportionate rises in blood levels and toxicity
• Sometimes free (unbound) concentrations need to be
measured - eg hypoalbuminaemia, pregnancy

46. Digoxin
• Has variable bioavailability
• Has variable clearance (by kidney) - remember the elderly
• Drug interactions are fairly common
• Relationship between concentration and effect is not
constant - concentrations soon after dosing are difficult to
interpret. Range is approx 1 to 2 nmol/L
• Patients may become more ‘sensitive’ to a given
concentration - eg hypokalalaemia, hypothyroidism
• In atrial fibrillation titrate against the ventricular rate
• Concentrations should be measure at least 6-8 hours after
the last dose

47. Cyclosporin
• Used as immunosuppressant in transplant
rejection
• Low therapeutic index and toxicity (kidney) is
severe
• Interactions are common - eg calcium channel
antagonists
• Plasma range 50-300 mg/L

48. Theophylline
• Declining use in asthma
• Very narrow therapeutic index: 55 - 110
umol/L (should be lower)
• At the high end toxicity is common
• Toxicity is severe - GI, neuro, cardiac
• Interactions are common - erythromycin,
cyclosporin, cimetidine, smoking

49. Gentamicin
• Practice is changing - trend to once/daily
dosing
• Toxicity relates to trough concentrations,
particularly with prolonged therapy
• Desirable range:
– peak 6 - 10 mg/L
– trough 1-2 mg/L