THERAPEUTIC DRUG

MONITORING
(TDM)
Dr. Chaichan Sangdee
Department of Pharmacology
Faculty of Medicine
Chiang Mai University

DO ALL DRUGS NEED

Drugs
that do not need TDM:
TDM?

Drugs that used for treating diseases of

which their clinical end points can easily be
monitored, e.g., BP, HR, cardiac rhythm,
blood sugar, blood cholesterol and
triglycerides, urine volume, body temperature,
inflammation, pain, headache, etc.
Drugs whose serum concentrations do not
correlate with therapeutic or toxic effects.
Drugs with less complicated
pharmacokinetics.
Drugs that used to treat less complicated or
not life threatening diseases

COMMONLY MONITORED
DRUGS

1. Bronchodilators: Theophylline
2. Antibiotics
: Aminoglycosides - Gentamicin,
Amikacin
: Others - Vancomycin
3.
Immunosuppressants:
Cyclosporine
4. Anticancers: Methotrexate

COMMONLY MONITORED
DRUGS (contd)

5. Antiepileptics: Phenobarbital,
Phenytoin,
Carbamazepine, Valproate
6. Cardiac Drugs : Digoxin*,
Procainamide,
Lidocaine
7. Psychoactive Drugs: Lithium, TCA
8. Analgesics: Aspirin, Paracetamol

CRITERIA FOR TDM

1. Assay methods
2. Narrow therapeutic range
3. Poor relationship between dose
and serum drug concentrations (S
DC)
4. Non-linear pharmacokinetics
5. Good relationship between serum
SDC and therapeutic/toxic effects

CRITERIA FOR TDM (contd)

6. Lack of therapeutic effects is

dangerous
7. Difficulty in interpreting signs and
symptoms of toxicity or
therapeutic failure or
in evaluating therapeutic responses
: Toxicity vs therapeutic failure
: Therapeutic responses

TDM ASSAY
METHODOLOGIES
1. EMIT: highly automated, rapid turnaround,
many assays available, homogenous,
moderate sensitivity but poor stability of
calibration curve
2. ELISA: highly automated, rapid
turnaround, moderate sensitivity but few
assays available, heterogenous
3. RIA: high sensitivity but long
turnaround,many
interferences, heterogenous, radiation
hazards

TDM ASSAY
METHODOLOGIES (contd)

4. FPIA: highly automated, rapid turnaround,

many assays available, stability of
reagents
and calibration curves, moderate
sensitivity,
homogenous
5. HPLC: highest sensitivity, most assays
available, least expensive but long
turnaround,
requires highly trained personnel

TYPES OF ASSAY REQUIRED

Total drug conc.
Free drug conc.
Metabolites

APPROPRIATE USE OF TDM

1. Maximizing & speeding up efficacy
2. Minimizing toxicity
3. Patient's drug history uncertain
4. Poor response to initial Rx or
deterioration
after good response
5. When hepatic or renal function is
changing

APPROPRIATE USE OF TDM

(contd)
6. During drug interactions

7. Individualizing therapy and

dosage regimen
adjustment
8. To make decision about future
therapy
9. Pharmacokinetic profiling

FACTORS AFFECTING SDC &

INTERPRETATION OF SDC

1. Disease states: renal, liver, cardiac,

thyroid
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

GUIDELINES FOR SAMPLING

TIME
Establish that SDC is at steady-state

Ensure
complete
absorption
and
distribution
Reasons for TDM
All except aminoglycosides
: suspect toxicity - peak SDC
: suspect failure or noncompliance - trough
SDC
Aminoglycosides
: suspect toxicity - peak & trough SDC
: suspect failure or noncompliance : peak
SDC

CLINICAL USEFULNESS OF
TDM
MAXIMIZING EFFICACY
- Epileptic pt. vs Phenytoin
- Burn pt. vs Gentamicin
- Asthmatic pt. vs Theophylline
- Life-saving in serious
situations

CLINICAL USEFULNESS OF TDM

(contd)

AVOIDING TOXICITY
- Overdose
- Differentiate adverse effects from disease
states
: Digoxin toxicity vs ventricular
arrhythmias
: Digoxin toxicity vs hypo-K or hyperCa
- Altered pharmacokinetics

CLINICAL USEFULNESS OF
TDM (contd)

IDENTIFYING THERAPEUTIC
FAILURE
- Non-compliance
- Subtherapeutic dose
- Bioavailability problem
- Malabsorption
- Drug interactions

CLINICAL USEFULNESS OF
TDM
(contd)

FACILITATING ADJUSTMENT OF
DOSAGE
New dose = Old dose X Desired
Css/Old Css
Clearance : obtain a Css

peak

MD
= Css X Cl
T1/2 or Dosing interval : obtain a
& trough

CLINICAL USEFULNESS OF
TDM (contd)
FACILITATING
THERAPEUTIC
EFFECTS
- Target drug conc.:
Antiepileptics
- Dosage adjustment

COST-BENIFITS OF TDM

HOSPITAL
- Reduce hospital congestion
- Increase quality of Rx and service
- Economic consideration
- Personnel: research, promotion &
self
esteem
- Medico-legal aspects

BENIFITS OF TDM (contd)

PATIENT CARE
- Decrease duration of stay in
hospital
- Receive safer and more
effective Rx
- More economic
- Increased productivity
- Improve quality of life

COST-EFFECTIVENESS OF
METHODOLOGY
Economic consideration

: Building cost
: Maintenance costs of
equipment
: Equipment depreciation costs
: Medical supplies
: Salaries

COST-EFFECTIVENESS OF
METHODOLOGY (contd)

Expenses of TDM measurement vs

cost of extended medical care
Facilitating
future
roles
of
pharmacists & other
personnel
: Clinical pharmacy
: Active roles in patient care
: Research & Development (R&D)

COST-EFFECTIVENESS OF
METHODOLOGY (contd)

Before setting up TDM

How many drugs should be monitored?
How many times a day should samples
can be sent for measurement?
One a day, twice a day or around the
clock
Personnels needed
Equipment needed
Billling system
Shipping of reagents

PROBLEMS OF TDM
Hospital
personnel do not know the
SERVICE

existence
of TDM service
Physicians do not understand the principles,
benefits, and the limitations of TDM
service
Inappropriate sampling times
Do not state the indication of TDM
Insufficient patients history and other
necessary data
No consultation when problems arise

REQUEST FORM OF TDM

Patient Name............................................. Date...............................................
HN........................................................
Age.................................. Sex................................. Wt...................................... Ht......................
...................................
Ward.............................................Ordered by....................................................... Phone No.....
.....................................
DRUG LEVEL REQUESTED..............................................................................................................
....................................
REASON FOR REQUEST :
( ) Suspected toxicity
( ) Compliance
( ) Therapeutic confirmation
( ) Absence of therapeutic response
Please indicate when level is needed :
( ) within 24 h
( ) within 1-2 h
( ) stat
( ) others........................
TIME AND DATE OF LAST DOSE :
Date....................
Route : IV, IM, SC, PO, Others...........................
Time....................
Dose.......................... Freq..................................
THIS DRUG LEVEL IS FOR :
SAMPLING TIME :
( ) Trough or predose level
Date....................... Time.........................
( ) Peak level
Date....................... Time................
........

Drug

Time to steady state

Therapeutic range

Sampling time
(mg/L)

Aminoglycosides
Amikacin
Adults
(< 30 y): ~ 2.5-15 h Peak 0.5-1 h after IV infusion
Peak 15-25, Trough< 5
Kanamycin
(> 30 y): ~ 7.5-75 h
(1 h after IM)
Gentamicin Children: ~ 2.5-12.5 h
Dibekacin
Neonate: ~ 10-45 h
Netilmicin
Tobramicin
Streptomycin
10-15 h
Peak 1-2 h after IM
Peak 15-40
Trough < 5
Antineoplastics
Methotrexate
12-24 h
Depend on dose &
48 h > 0.5 umol/L

24 h > 5 umol/L
duration of infusion

Drug

Time to steady state

Therapeutic range

Sampling time
(mg/L)

Antiarrhythmics
Disopyramide
1-2 d
Trough
2-5
Lidocaine
1 h after LD
2 h after LD
1.5-5
5-10 h (no LD)
6-12 h (no LD)
Procainamide/NAPA
Adult (no LD)
Immediately after IV LD
Procainamide 4-10
: normal renal 15-25 h 2 h after start of IV infusion,
NAPA 6-20
: renal insuff 30-65 h
once more during 24 h
period
Oral: peak (1-4 h) and trough
Quinidine
2d
Trough

Drug

Time to steady state

Therapeutic range

Antiepileptics
Carbamazepine
2-6 d
4-10
Ethosuximide
1-2 wk
40-100
Phenobarbital
3 wk
15-40
Phenytoin
7d
10-20
Valproate

2-3 d
50-100

Bronchodilators

Sampling time
(mg/L)

Trough
Any time
Any time
2-4 h
Trough

Drug
Analgesics
Aspirin

Time to steady state

Therapeutic range

Sampling time

1-5 d
150-300 (antiinflam.)

1-3 h

(mg/L)

250-400 (rheumatic fev)

Paracetamol
4 h postingestion > 200
toxicity
12 h postingestion > 50
Psychoactive Drugs
Amitriptyline
3-8 d
150-250 ug/L
Imipramine
2-5 d
150-250 ug/L

Trough
Trough