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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:

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therapeutic drug monitoring tdm

THERAPEUTIC DRUG MONITORING (TDM)

Dr. Chaichan Sangdee

Department of Pharmacology

Faculty of Medicine

Chiang Mai University

do all drugs need tdm
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
COMMONLY MONITORED DRUGS

1. Bronchodilators: Theophylline

2. Antibiotics

: Aminoglycosides - Gentamicin, Amikacin

: Others - Vancomycin

3. Immunosuppressants: Cyclosporine

4. Anticancers: Methotrexate

commonly monitored drugs cont d
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

criteria for tdm
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 cont d
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

tdm assay methodologies
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 cont d
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

types of assay required
TYPES OF ASSAY REQUIRED
  • Total drug conc.
  • Free drug conc.
  • Metabolites
appropriate use of tdm
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 cont d
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

factors affecting sdc interpretation of sdc
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
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
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 cont d
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

clinical usefulness of tdm cont d16
CLINICAL USEFULNESS OF TDM (cont’d)
  • IDENTIFYING THERAPEUTIC FAILURE

- Non-compliance

- Subtherapeutic dose

- Bioavailability problem

- Malabsorption

- Drug interactions

clinical usefulness of tdm cont d17
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

clinical usefulness of tdm cont d18
CLINICAL USEFULNESS OF TDM (cont’d)
  • FACILITATING THERAPEUTIC EFFECTS

- Target drug conc.: Antiepileptics

- Dosage adjustment

cost benifits of tdm
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 cont d
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

cost effectiveness of methodology
COST-EFFECTIVENESS OF METHODOLOGY
  • Economic consideration

: Building cost

: Maintenance costs of equipment

: Equipment depreciation costs

: Medical supplies

: Salaries

cost effectiveness of methodology cont d
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)

cost effectiveness of methodology cont d23
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
problems of tdm service
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
slide25

REQUEST FORM OF TDMPatient 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............................…………..

slide26

Drug Time to steady state Sampling time Therapeutic range (mg/L)AminoglycosidesAmikacin 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 hDibekacin Neonate: ~ 10-45 h NetilmicinTobramicin Streptomycin 10-15 h Peak 1-2 h after IM Peak 15-40 Trough < 5AntineoplasticsMethotrexate 12-24 h Depend on dose & 24 h > 5umol/L duration of infusion 48 h > 0.5 umol/L 72 h > 0.05 umol/LImmunosuppressantsCyclosporine 1 d Day 3 or 4 of therapy, then 100-200 ug/L twice weekly for few weeks and reduce to every 1-2 mo

slide27

Drug Time to steady state Sampling time Therapeutic range (mg/L)AntiarrhythmicsDisopyramide 1-2 d Trough 2-5Lidocaine 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 troughQuinidine 2 d Trough 2-5Cardiac GlycosidesDigitoxin 1 mo 8-24 h 13-25 ug/L Digoxin 5-7 d 8-24 h 0.9-2.2 ug/L May be longer in renal insufficiency

slide28

Drug Time to steady state Sampling time Therapeutic range (mg/L)AntiepilepticsCarbamazepine 2-6 d Trough 4-10Ethosuximide 1-2 wk Any time 40-100Phenobarbital 3 wk Any time 15-40Phenytoin 7 d 2-4 h 10-20Valproate 2-3 d Trough 50-100BronchodilatorsTheophylline 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 beginning therapy Newborn: 120 h Oral: peak Premy: 150 h 2 h after rapid release prep 4 h after sustained release prep

slide29

Drug Time to steady state Sampling time Therapeutic range (mg/L)AnalgesicsAspirin 1-5 d 1-3 h 150-300 (antiinflam.) 250-400 (rheumatic fev) Paracetamol 4 h postingestion > 200 toxicity 12 h postingestion > 50 Psychoactive DrugsAmitriptyline 3-8 d Trough 150-250 ug/LImipramine 2-5 d Trough 150-250 ug/LNortriptyline 4-20 d Trough 50-150 ug/LLithium 3-7 d Trough 0.6-1.2 mEq/L