Description
The presentation includes TDM or Therapeutic Drug Monitoring by analysing topics like purpose, Pharmacokinetic Considerations, Methodological Difficulties.
THERAPEUTIC DRUG MONITORING (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 1. Bronchodilators: Theophylline 2. Antibiotics : Aminoglycosides - Gentamicin, Amikacin : Others - Vancomycin 3. Immunosuppressants: Cyclosporine 4. Anticancers: Methotrexate 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 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 (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 ? ? ? 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 (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 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 (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’d)
? IDENTIFYING THERAPEUTIC FAILURE - Non-compliance - Subtherapeutic dose - Bioavailability problem - Malabsorption - Drug interactions
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’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 esteem - Medico-legal aspects
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
? Economic consideration : Building cost : Maintenance costs of equipment : Equipment depreciation costs : Medical supplies : Salaries
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’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 ? 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
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............................…………..
Drug Aminoglycosides Amikacin Kanamycin Gentamicin Dibekacin Netilmicin Tobramicin Streptomycin
Time to steady state
Sampling time
Therapeutic range
(mg/L)
Adults (< 30 y): ~ 2.5-15 h (> 30 y): ~ 7.5-75 h Children: ~ 2.5-12.5 h Neonate: ~ 10-45 h
10-15 h
Peak 0.5-1 h after IV infusion Peak 15-25, Trough< 5 (1 h after IM)
Peak 1-2 h after IM Trough < 5
Peak 15-40
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 Day 3 or 4 of therapy, then twice weekly for few weeks and reduce to every 1-2 mo 100-200 ug/L
Immunosuppressants Cyclosporine 1d
Drug
Time to steady state
Sampling time
Therapeutic range (mg/L) 2-5 1.5-5 Procainamide 4-10
Antiarrhythmics Disopyramide 1-2 d Trough Lidocaine 1 h after LD 2 h after LD 5-10 h (no LD) 6-12 h (no LD) Procainamide/NAPA Adult (no LD) Immediately after IV LD : 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 Digoxin 5-7 d 8-24 h 8-24 h May be longer in renal insufficiency 0.9-2.2 ug/L 13-25 ug/L
Drug Antiepileptics Carbamazepine Ethosuximide 1-2 wk Phenobarbital 3 wk Phenytoin 7d Valproate 2-3 d
Time to steady state Sampling time 2-6 d Any time Any time 2-4 h Trough Trough 40-100 15-40 10-20 50-100
Therapeutic range (mg/L) 4-10
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 beginning therapy Newborn: 120 h Oral: peak Premy: 150 h 2 h after rapid release prep 4 h after sustained release prep
Drug Analgesics Aspirin Paracetamol toxicity Psychoactive Drugs Amitriptyline Imipramine Nortriptyline 4-20 d Lithium 3-7 d
Time to steady state Sampling time 1-5 d 1-3 h
Therapeutic range (mg/L) 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
3-8 d 2-5 d Trough Trough
Trough
doc_116250852.ppt
The presentation includes TDM or Therapeutic Drug Monitoring by analysing topics like purpose, Pharmacokinetic Considerations, Methodological Difficulties.
THERAPEUTIC DRUG MONITORING (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 1. Bronchodilators: Theophylline 2. Antibiotics : Aminoglycosides - Gentamicin, Amikacin : Others - Vancomycin 3. Immunosuppressants: Cyclosporine 4. Anticancers: Methotrexate 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 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 (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 ? ? ? 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 (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 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 (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’d)
? IDENTIFYING THERAPEUTIC FAILURE - Non-compliance - Subtherapeutic dose - Bioavailability problem - Malabsorption - Drug interactions
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’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 esteem - Medico-legal aspects
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
? Economic consideration : Building cost : Maintenance costs of equipment : Equipment depreciation costs : Medical supplies : Salaries
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’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 ? 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
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............................…………..
Drug Aminoglycosides Amikacin Kanamycin Gentamicin Dibekacin Netilmicin Tobramicin Streptomycin
Time to steady state
Sampling time
Therapeutic range
(mg/L)
Adults (< 30 y): ~ 2.5-15 h (> 30 y): ~ 7.5-75 h Children: ~ 2.5-12.5 h Neonate: ~ 10-45 h
10-15 h
Peak 0.5-1 h after IV infusion Peak 15-25, Trough< 5 (1 h after IM)
Peak 1-2 h after IM Trough < 5
Peak 15-40
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 Day 3 or 4 of therapy, then twice weekly for few weeks and reduce to every 1-2 mo 100-200 ug/L
Immunosuppressants Cyclosporine 1d
Drug
Time to steady state
Sampling time
Therapeutic range (mg/L) 2-5 1.5-5 Procainamide 4-10
Antiarrhythmics Disopyramide 1-2 d Trough Lidocaine 1 h after LD 2 h after LD 5-10 h (no LD) 6-12 h (no LD) Procainamide/NAPA Adult (no LD) Immediately after IV LD : 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 Digoxin 5-7 d 8-24 h 8-24 h May be longer in renal insufficiency 0.9-2.2 ug/L 13-25 ug/L
Drug Antiepileptics Carbamazepine Ethosuximide 1-2 wk Phenobarbital 3 wk Phenytoin 7d Valproate 2-3 d
Time to steady state Sampling time 2-6 d Any time Any time 2-4 h Trough Trough 40-100 15-40 10-20 50-100
Therapeutic range (mg/L) 4-10
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 beginning therapy Newborn: 120 h Oral: peak Premy: 150 h 2 h after rapid release prep 4 h after sustained release prep
Drug Analgesics Aspirin Paracetamol toxicity Psychoactive Drugs Amitriptyline Imipramine Nortriptyline 4-20 d Lithium 3-7 d
Time to steady state Sampling time 1-5 d 1-3 h
Therapeutic range (mg/L) 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
3-8 d 2-5 d Trough Trough
Trough
doc_116250852.ppt