THERAPEUTIC DRUG

MONITORING
(TDM)

Rahmad Abdillah

Department of Pharmacology &

Clinical Pharmacy
Measurement of serum concentration of medications
to obtain optimal concentration and benefit to patient
with minimal toxic adverse effects

Do all drugs need TDM? NO!

The uses of TDM
• Maximizing and speeding up efficacy
• Minimizing toxicity
• Patient’s drug history uncertain
• Poor response to initial drug response or
deterioration after good response
• When hepatic or renal function is changing
• During drug interactions
• Individualizing therapy and dosage regimen
adjustment
Indications of TDM
• The consequences of overdosing and
underdosing are serious.
• There is a small difference between a
therapeutic and toxic dose.
• There is a change in the patient's physiologic
state that may unpredictably affect circulating
drug concentrations.
• A drug interaction may be occurring.
• TDM helps in monitoring patient compliance.
4
 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.
COMMONLY MONITORED
DRUGS
1. Bronchodilators:
Theophylline
2. Antibiotics
: Aminoglycosides -
Gentamicin, Amikacin
: Others - Vancomycin
3. Immunosuppressants:
 COMMONLY MONITORED
DRUGS
5. Antiepileptics: Phenobarbital,
Phenytoin,
Carbamazepine, Valproate
6. Cardiac Drugs : Digoxin*,
Procainamide,
Lidocaine
7. Psychoactive Drugs: Lithium,
 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
 CRITERIA FOR TDM
(cont’d)
6. Lack of therapeutic effects is
dangerous
7. Difficulty in interpreting
signs and
symptoms of toxicity or
therapeutic failure or
in evaluating therapeutic
 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
 TDM ASSAY
METHODOLOGIES
4. FPIA: highly automated, rapid
turnaround,
many assays available,
stability of reagents
and calibration curves,
moderate sensitivity,
homogenous
5. HPLC: highest sensitivity, most
assays
 TYPES OF ASSAY REQUIRED

• Total drug conc.

• Free drug conc.
• Metabolites
 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
 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
 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
• AVOIDING TOXICITY
- Overdose
- Differentiate adverse effects
from disease
states
: Digoxin toxicity vs
ventricular arrhythmias
 CLINICAL USEFULNESS OF
TDM
• IDENTIFYING THERAPEUTIC
FAILURE
- Non-compliance
- Subtherapeutic dose
- Bioavailability problem
- Malabsorption
- Drug interactions
 CLINICAL USEFULNESS OF
TDM
• 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 :
 CLINICAL USEFULNESS OF
TDM (cont’d)
• 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
 BENIFITS OF TDM
• PATIENT CARE
- Decrease duration of stay in
hospital
- Receive safer and more
effective Rx
- More economic
- Increased productivity
 COST-EFFECTIVENESS OF
METHODOLOGY
• Economic consideration
: Building cost
: Maintenance costs of
equipment
: Equipment depreciation
costs
: Medical supplies
 COST-EFFECTIVENESS OF
METHODOLOGY
• Expenses of TDM
measurement vs cost of
extended medical care
• Facilitating future roles of
pharmacists & other
personnel
: Clinical pharmacy
 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 patient’s history
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
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
DibekacinNeonate: ~ 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 &
24 h > 5 umol/L
duration of infusion 48 h
> 0.5 umol/L
72 h
> 0.05 umol/L
Immunosuppressants
 (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 2-5

Cardiac Glycosides
Digitoxin 1 mo 8-24 h 13-
25 ug/L
Digoxin 5-7 d 8-24 h 0.9-
 (mg/L)
Antiepileptics
Carbamazepine 2-6 d Trough 4-10
Ethosuximide 1-2 wk Any time 40-
100
Phenobarbital 3 wk Any time 15-
40
Phenytoin 7d 2-4 h 10-
20

Valproate 2-3 d Trough 50-

100

Bronchodilators
Theophylline Adult: 2 d IV: 30 min after IV LD
10-20
Children: 1-2 d : 4-6 h after beginning
therapy
Infants: 1-5 d : 12-18 h after
 (mg/L)
Analgesics
Aspirin 1-5 d 1-3 h 150-
300 (antiinflam.)
250-
400 (rheumatic fev)
Paracetamol 4h
postingestion > 200
toxicity 12 h
postingestion > 50

Psychoactive Drugs
Amitriptyline 3-8 d Trough
150-250 ug/L
Imipramine 2-5 d Trough 150-
250 ug/L
Nortriptyline 4-20 d Trough 50-
150 ug/L
Lithium 3-7 d Trough 0.6-
THE END
Homework
• Find an international journal/paper about
clinical therapeutic drug monitoring for a
spesific drug and make a review!