THERAPEUTIC DRUG MONITORING

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

DO ALL DRUGS NEED TDM?

Drugs that do not need 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 (SDC)
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 hyper-Ca
- 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
MD = Css X Cl
T1/2 or Dosing interval : obtain a peak
& 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 SERVICE

Hospital personnel do not know the 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

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........................
DOES THE PATIENT HAVE ORGAN-SYSTEM DAMAGE ?
( ) Renal
( ) Hepatic
( ) Cardiac
( ) GI
( ) Endocrine
( )
Others.........................
OTHER DRUG(S) PATIENT IS TAKING :...........................................................................................................
DRUG LEVEL & USUAL THERAPEUTIC RANGE.............................................................................................
INTERPRETATION..................................................................................................................................................
................................................................................................................................
..............................................
Date.......................... Technologist................................. Time..............................

Drug

Time to steady state

Aminoglycosides
Amikacin
Adults
(< 30 y): ~ 2.5-15 h
Kanamycin
(> 30 y): ~ 7.5-75 h
Gentamicin Children: ~ 2.5-12.5 h
Dibekacin
Neonate: ~ 10-45 h
Netilmicin
Tobramicin
Streptomycin 10-15 h
Antineoplastics
Methotrexate 12-24 h

Immunosuppressants
Cyclosporine 1 d

Sampling time

Therapeutic range
(mg/L)

Peak 0.5-1 h after IV infusion Peak 15-25, Trough< 5

(1 h after IM)

Peak 1-2 h after IM

Peak 15-40
Trough < 5

Depend on dose &

duration of infusion

24 h > 5 umol/L
48 h > 0.5 umol/L
72 h > 0.05 umol/L

Day 3 or 4 of therapy, then 100-200 ug/L

twice weekly for few weeks
and reduce to every 1-2 mo

Drug

Time to steady state

Antiarrhythmics
Disopyramide 1-2 d
Lidocaine
1 h after LD
5-10 h (no LD)
Procainamide/NAPA
Adult (no LD)
: normal renal 15-25 h
: renal insuff 30-65 h
Quinidine

2d

Sampling time

Therapeutic range
(mg/L)

Trough
2 h after LD
6-12 h (no LD)

2-5
1.5-5

Immediately after IV LD
Procainamide 4-10
2 h after start of IV infusion, NAPA 6-20
once more during 24 h period
Oral: peak (1-4 h) and trough
Trough
2-5

Cardiac Glycosides
Digitoxin
1 mo
8-24 h
Digoxin
5-7 d
8-24 h
May be longer in renal
insufficiency

13-25 ug/L
0.9-2.2 ug/L

Drug

Time to steady state Sampling time

Therapeutic range
(mg/L)

Antiepileptics
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin

2-6 d
1-2 wk
3 wk
7d

Trough
Any time
Any time
2-4 h

4-10
40-100
15-40
10-20

Valproate

2-3 d

Trough

50-100

Bronchodilators
Theophylline
Adult: 2 d
Children: 1-2 d
Infants: 1-5 d
Newborn: 120 h
Premy: 150 h

IV: 30 min after IV LD

10-20
: 4-6 h after beginning therapy
: 12-18 h after beginning therapy
Oral: peak
2 h after rapid release prep
4 h after sustained release prep

Drug

Time to steady state Sampling time

Therapeutic range
(mg/L)

Analgesics
Aspirin

1-5 d

1-3 h

150-300 (antiinflam.)
250-400 (rheumatic fev)
4 h postingestion > 200
12 h postingestion > 50

Trough

150-250 ug/L
150-250 ug/L
50-150 ug/L
0.6-1.2 mEq/L

Paracetamol
toxicity
Psychoactive Drugs
Amitriptyline 3-8 d
Imipramine
2-5 d
Nortriptyline 4-20 d
Lithium
3-7 d

Trough
Trough
Trough