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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?. Drugs that do not need TDM:

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THERAPEUTIC DRUG MONITORING (TDM)

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  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. 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 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............................…………..

  26. 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

  27. 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

  28. 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

  29. 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

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