THERAPEUTIC DRUG MONITORING TDM Dr Chaichan Sangdee

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

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

DRUGS. 1 Bronchodilators: Theophylline. 2 Antibiotics : Aminoglycosides Gentamicin, Amikacin : Others - Vancomycin. 3 Immunosuppressants:

DRUGS (cont’d(. 5 Antiepileptics: Phenobarbital, Phenytoin, Carbamazepine, Valproate. 6 Cardiac Drugs : Digoxin*, Procainamide, Lidocaine. 7 Psychoactive Drugs:

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

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

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

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

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

TDM. 1 Maximizing & speeding up efficacy. 2 Minimizing toxicity. 3 Patient's drug history uncertain. 4 Poor response to initial Rx or deterioration

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 + & Ca++ vs K. 6 Drug interactions

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

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

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 T 1/2 or Dosing interval :

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

BENIFITS OF TDM (cont’d( § PATIENT CARE - Decrease duration of stay in hospital - Receive safer and more effective Rx - More economic - Increased productivity

METHODOLOGY § Economic consideration : Building cost : Maintenance costs of equipment : Equipment depreciation costs : Medical supplies

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

COST-EFFECTIVENESS OF METHODOLOGY (cont’d( § Before setting up TDM l How many drugs should be monitored? l How many times a day should samples can be sent for measurement? • One a day, twice a day or around the clock § Personnels needed

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

( ) 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. . …………. . . .

(< 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 > 5 umol/L > 0. 5 umol/L Depend on dose & duration of infusion 72 h > 0. 05 umol/L Immunosuppressants Cyclosporine 1 d then 100 -200 ug/L 48 h Day 3 or 4 of therapy, twice weekly for few weeks and reduce to every 1 -2 mo

2 -5 Lidocaine 1 h after LD 5 -10 h (no LD) Procainamide/NAPA Adult (no LD) Procainamide 4 -10 : normal renal 15 -25 h NAPA 6 -20 : renal insuff 30 -65 h Quinidine 2 d Cardiac Glycosides Digitoxin 1 mo 25 ug/L Digoxin 5 -7 d 2. 2 ug/L May be longer in renal insufficiency 2 h after LD 6 -12 h (no LD) 1. 5 -5 Immediately after IV LD 2 h after start of IV infusion, once more during 24 h period Oral: peak (1 -4 h) and trough Trough 2 -5 8 -24 h 130. 9 -

100 Phenobarbital 40 Phenytoin 20 Valproate 100 3 wk Any time 15 - 7 d 2 -4 h 10 - 2 -3 d Trough 50 - 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

300 (antiinflam. ) 250400 (rheumatic fev) Paracetamol postingestion > 200 toxicity postingestion > 50 Psychoactive Drugs Amitriptyline 3 -8 d 150 -250 ug/L Imipramine 2 -5 d ug/L Nortriptyline 4 -20 d 150 ug/L Lithium 3 -7 d 1. 2 m. Eq/L 4 h 12 h Trough 150 -250 Trough 50 - Trough 0. 6 -