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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’d):

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

CLINICAL USEFULNESS OF TDM (cont’d):

CLINICAL USEFULNESS OF TDM (cont’d) FACILITATING ADJUSTMENT OF DOSAGE New dose = Old dose X Desired C ss /Old C ss Clearance : obtain a C ss MD = Css X Cl T 1/2 or Dosing interval : obtain a peak & trough

CLINICAL USEFULNESS OF TDM (cont’d):

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 : Maintena n ce 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’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:

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 s ampling 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............................………….. :

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 Time to steady state Sampling time Therapeutic range (mg/L) 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 Dibekacin Neonate: ~ 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 Cyclosporine 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:

Drug Time to steady state Sampling time Ther a peutic range (mg/L) 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 Dibekacin Neonate: ~ 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 u mol/L duration of infusion 48 h > 0.5 u mol/L 72 h > 0.05 u mol/L Immunosuppressants Cyclosporine 1 d D ay 3 or 4 of therapy, then 100-200 u g/L twice weekly for few weeks and reduce to every 1-2 m o

Drug Time to steady state Sampling time Therapeutic range (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 2 d Trough 2-5 Cardiac Glycosides Digitoxin 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 :

Drug Time to steady state Sampling time Ther a peutic range (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 2 d Trough 2-5 Cardiac Glycosides Digitoxin 1 mo 8-24 h 13-25 u g/L Digoxin 5-7 d 8-24 h 0.9-2.2 u g/L May be longer in renal i nsuff iciency

Drug Time to steady state Sampling time Therapeutic range (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 7 d 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 beginning therapy Newborn: 120 h Oral: peak Premy: 150 h 2 h after rapid release prep 4 h after sustained release prep:

Drug Time to steady state Sampling time Ther a peutic range (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 7 d 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 beginning therapy Newborn: 120 h Oral: peak Premy: 150 h 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) Paracetamol 4 h 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 0.6-1.2 mEq/L :

Drug Time to steady state Sampling time Ther a peutic range (mg/L) Analgesics Aspirin 1-5 d 1-3 h 150-300 (antiinfl a m . ) 250-400 (rheumatic fev) Paracetamol 4 h postingestion > 200 toxicity 12 h postingestion > 50 Psychoactive Drugs Amitriptyline 3-8 d Trough 150-250 u g/L Imipramine 2-5 d Trough 150-250 u g/L Nortriptyline 4-20 d Trough 50-150 u g/L Lithium 3-7 d Trough 0.6-1.2 mEq/L