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

2. 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

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

4. COMMONLY MONITORED DRUGS (cont’d)
5. Antiepileptics: Phenobarbital, Phenytoin,
Carbamazepine, Valproate
6. Cardiac Drugs : Digoxin*, Procainamide,
Lidocaine
7. Psychoactive Drugs: Lithium, TCA
8. Analgesics: Aspirin, Paracetamol

5. 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

6. 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 responses
: Toxicity vs therapeutic failure
: Therapeutic responses

7. 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

8. TDM ASSAY METHODOLOGIES (cont’d)
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

9. TYPES OF ASSAY REQUIRED
Total drug conc.
Free drug conc.
Metabolites

10. 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

11. APPROPRIATE USE OF TDM (cont’d)
6. During drug interactions
7. Individualizing therapy and dosage regimen
adjustment
8. To make decision about future therapy
9. Pharmacokinetic profiling

12. 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

13. 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

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

15. CLINICAL USEFULNESS OF TDM (cont’d)
AVOIDING TOXICITY
- Overdose
- Differentiate adverse effects from disease
states
: Digoxin toxicity vs ventricular arrhythmias
: Digoxin toxicity vs hypo-K or hyper-Ca
- Altered pharmacokinetics

16. CLINICAL USEFULNESS OF TDM (cont’d)
IDENTIFYING THERAPEUTIC FAILURE
- Non-compliance
- Subtherapeutic dose
- Bioavailability problem
- Malabsorption
- Drug interactions

17. CLINICAL USEFULNESS OF TDM (cont’d)
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

18. CLINICAL USEFULNESS OF TDM (cont’d)
FACILITATING THERAPEUTIC EFFECTS
- Target drug conc.: Antiepileptics
- Dosage adjustment

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

20. BENIFITS OF TDM (cont’d)
PATIENT CARE
- Decrease duration of stay in hospital
- Receive safer and more effective Rx
- More economic
- Increased productivity
- Improve quality of life

21. COST-EFFECTIVENESS OF METHODOLOGY
Economic consideration
: Building cost
: Maintenance costs of equipment
: Equipment depreciation costs
: Medical supplies
: Salaries

22. COST-EFFECTIVENESS OF METHODOLOGY (cont’d)
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)

23. COST-EFFECTIVENESS OF METHODOLOGY (cont’d)
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

24. 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 and other
necessary data
No consultation when problems arise

25. REQUEST FORM OF TDM Patient Name. Date. HN. Age. Sex. Wt. Ht. Ward
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 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 …………..

26. Drug. Time to steady state Sampling time. Therapeutic range
Drug Time to steady state Sampling time Therapeutic range (mg/L) Aminoglycosides Amikacin Adults (< 30 y): ~ h Peak h after IV infusion Peak 15-25, Trough< 5 Kanamycin (> 30 y): ~ h (1 h after IM) Gentamicin Children: ~ h Dibekacin Neonate: ~ h Netilmicin Tobramicin Streptomycin h Peak 1-2 h after IM Peak Trough < 5 Antineoplastics Methotrexate h Depend on dose & h > 5 umol/L duration of infusion h > 0.5 umol/L h > 0.05 umol/L Immunosuppressants Cyclosporine 1 d Day 3 or 4 of therapy, then ug/L twice weekly for few weeks and reduce to every 1-2 mo

27. Drug. Time to steady state Sampling time. Therapeutic range
Drug Time to steady state Sampling time Therapeutic range (mg/L) Antiarrhythmics Disopyramide 1-2 d Trough Lidocaine h after LD 2 h after LD h (no LD) h (no LD) Procainamide/NAPA Adult (no LD) Immediately after IV LD Procainamide : normal renal h 2 h after start of IV infusion, NAPA : renal insuff h once more during 24 h period Oral: peak (1-4 h) and trough Quinidine d Trough Cardiac Glycosides Digitoxin mo h ug/L Digoxin d h ug/L May be longer in renal insufficiency

28. Drug. Time to steady state. Sampling time. Therapeutic range
Drug Time to steady state Sampling time Therapeutic range (mg/L) Antiepileptics Carbamazepine 2-6 d Trough Ethosuximide wk Any time Phenobarbital wk Any time Phenytoin d h Valproate d Trough Bronchodilators Theophylline Adult: 2 d IV: 30 min after IV LD Children: 1-2 d : 4-6 h after beginning therapy Infants: 1-5 d : h after beginning therapy Newborn: 120 h Oral: peak Premy: 150 h 2 h after rapid release prep h after sustained release prep

29. Drug. Time to steady state. Sampling time. Therapeutic range
Drug Time to steady state Sampling time Therapeutic range (mg/L) Analgesics Aspirin d h (antiinflam.) (rheumatic fev) Paracetamol h postingestion > toxicity h postingestion > 50 Psychoactive Drugs Amitriptyline d Trough ug/L Imipramine d Trough ug/L Nortriptyline d Trough ug/L Lithium d Trough mEq/L