Therapeutic drug monitoring

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By: nagesh.adla (39 month(s) ago)

good morning sir, i m from andhra pradesh, india. i m doing my pharmD internship and ur slides make more informative and i request u please post me this to my mail and my mail id is nagesh.adla@gmail.com and i shall be thankful to u Dr. Tariq, Chemical pathologist

By: imnopqrst (50 month(s) ago)

Dear Dr Natasha Hope you would be in the best of your spirits. I am an assisstant professor in a medical college here in our capital city Islamabad, Pakistan. You have prepared this presentation nicely and I request you to post me this ppt on my e-mail address: chemtariq@yahoo.com I shall be highly obliged to you. Dr Tariq, Chemical Pathologist

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Therapeutic drug monitoring : 

DR.NATASHA Therapeutic drug monitoring

Definition : 

Definition Therapeutic drug monitoring (TDM) is generally defined as the clinical laboratory measurement of a chemical parameter that, with appropriate medical interpretation, will directly influence drug prescribing procedures By combining knowledge of pharmaceutics, pharmacokinetics, and pharmacodynamics, TDM enables the assessment of the efficacy and safety of a particular medication in a variety of clinical settings The goal of this process is to individualize therapeutic regimens for optimal patient benefit

Slide 3: 

A more appropriate description for the optimum use of drug concentration in clinical practice is TARGET CONCENTRATION INTERVENTION Surrogate effect-a convenient substitute for the desired therapeutic outcome Intervention in dose adjustment to achieve target drug concentration lowers variation in dose response relationship

Clinical usefulness of TDM : 

Clinical usefulness of TDM Maximize efficacy of drug Avoiding toxicity Identifying therapeutic failure Facilitating dose adjustment Facilitating therapeutic effects

Concept of TDM : 

Concept of TDM Based on the fact that there is a definable relationship between dose , plasma concentration,and therapeutic effect DOSE PLASMA CONCENTRATION THERAPEUTIC EFFECT

Slide 6: 

RATIONAL THERAPEUTICS PHARMACOKINETICS PHARMACODYNAMICS DOSE TARGET CONCENTRATION EFFECT

PK variables : 

PK variables Absorption-compliance -neonates,children,elderly -Variation in bioavailability -Metabolism Clearance-function of kidney,liver Vd-tissue or plasma binding Half life

PK-dose concentration effect : 

PK-dose concentration effect LOADING DOSE = Vd x Concentration MAINTENANCE DOSE = CL x Concentration HALF LIFE = 0.7 x Vd CL

PD variables : 

PD variables Maximum effect-helps to avoid the ineffectual increase of dose with the attendant risks of toxicity Sensitivity- eg decrease in sensitivity of digoxin in presence of hyperkalemia and an increase in hypokalemia

PD-concentration effect relation : 

PD-concentration effect relation Effect= Emax x pl. concentration EC50 + pl .concentration This above calculation does not consider adverse effects Target concentration can only be defined on basis of PD It is independent of the determinants of concentration ie.dose and PK

Therapeutic range vs target concentration : 

Therapeutic range vs target concentration

Slide 13: 

POPULATION THERAPEUTIC RANGE PATIENT TARGET CONCENTRATION

Monitoring drug therapy by clinical response : 

Monitoring drug therapy by clinical response

By in vitro tests : 

By in vitro tests

Target concentration strategy : 

Target concentration strategy

Indications for TDM : 

Indications for TDM 1.therapeutic failure-non compliance -genetic factors -difference in drug absorption 2.drugs with narrow therapeutic range -digoxin,lithium,quinidine Helps differentiate toxicity of drugs from a clinical condition Eg.digoxin toxicity may mimic certain symptoms of heart disease

Slide 18: 

3.Drugs with non linear kinetics-phenytoin 4.Drugs showing wide interindividual variation in metabolism-eg TCA 5.Drugs used for prophylactic purposes-eg phenytoin in epileptics,antiarrhythmics 6.Concomitant disease -to adjust dose depending on kinetic behavior 7.When endpoints are unreliable and clinical response is difficult to assess in a short period-phenytoin

Slide 19: 

8.Suspected drug- drug interactions-eg quinidine-digoxin 9.Check patient compliance-antitubercular drugs 10.Check bioavailability and bioequivalence of formulations 11.Individualisation of dose-paediatric , geriatric group,pregnancy 12.Therapy cessation monitoring

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 diseases that are not life threatening

TDM team : 

TDM team PATIENT

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............................…………..

ANALYTICAL METHODOLOGY : 

ANALYTICAL METHODOLOGY fundamental procedures: recovery from body fluids, tissues, and organs, separation from the biological components, identification of the species concerned quantification. COMPROMISE BETWEEN SPECIFICITY AND COST

AN IDEAL ANALYTICAL METHOD : 

AN IDEAL ANALYTICAL METHOD 1) distinguish between compounds of similar structure – unchanged drug and metabolites. 2) detect small amounts 3) be simple enough to use as a routine assay and 4) be unaffected by other drugs administered simultaneously 5) The assay results should be available quickly, preferably within 24 h of receiving the sample

METHODS-PAST AND PRESENT : 

METHODS-PAST AND PRESENT Prior to advent of GLC and HPLC, drug samples were analyzed by spectrophotometric methods. Drawbacks :large volume of samples, complex extraction procedures and interference by other compounds. THIN LAYER CHROMATOGRAPHY-Possess adequate resolutions for identifying many drugs. inability to quantify these drugs accurately and time consuming technique

HPLC AND GLC : 

HPLC AND GLC Highly specific, precise and sensitive. Multiple analyses can be done. drawbacks – i)extraction step required ii) slow, single serial analysis, iii) column degenerates with time and iv) complex analyses require considerable processing. HPLC technique is superior most

HPLC : 

HPLC

Radio immuno assay -RIA : 

Radio immuno assay -RIA sensitive, reasonably precise. Cross reactivity with other closely reacted drugs. not possible to find out the optically active isomer. Radiation hazards RELATIVELY EXPENSIVE

Slide 31: 

enzyme multiplied immunoassays(EMIT) ELISA Highly automated Rapid turnaround Moderate sensitivity multiple assay Heterogenous Poor stability of calibration curve Highly automated Rapid turnaround Moderate sensitivity Single assay heterogenous

Fluorescence polarization Immunoassay(FPIA) : 

Fluorescence polarization Immunoassay(FPIA) Combines competitive protein binding with fluorescence polarization. Advantages: accuracy precision Small volume 50 mcl short turn around time(30 min) Fully automated multiple samples assayed

Slide 33: 

Antibody technology-eg cyclosporine assays using poly/monoclonal parent drug specific antibodies Digoxin assays Quality control-maintaining a high standard and comparability Identifying potential sources of bias and unreliable analytical methods

Interferences with drug assays : 

Interferences with drug assays Altered plasma protein binding Presence of active metabolite Sterioisomerism-giving a racemic mixture is like giving 2 separate drugs TYPES OF ASSAY REQUIRED Total drug conc Free drug conc Metabolites

INTERPRETATION OF SERUM DRUG CONCENTRATION AND ADJUSTMENT OF DOSAGE : 

INTERPRETATION OF SERUM DRUG CONCENTRATION AND ADJUSTMENT OF DOSAGE always to be interpreted in the context of the clinical data. Therapeutic ranges are available but should be used only as a guide. require adjustment when other drugs with synergistic or antagonistic actions are administered concomitantly. Units used- Drug concentration--milligram/litre Volume of distribution-litre Clearance-litres/hour

Blood collection procedures : 

Blood collection procedures Drugs given in continuous infusion-collect sample from another site Drug concentration alteration with diurnal/posture Serum separator tubes more advantageous-except for TCA which may bind to the gel in the tubes Either plasma/serum samples exceptions-serum chloroquine concentration twice as high as plasma concentration(drug in platelets released after blood clots)

Plasma concentration not worth measuring : 

Plasma concentration not worth measuring Prothrombin time – Oral Anticoagulants. Blood Pressure – Antihypertensives. Body Weight – Diuretics. Blood Sugar – Hypoglycemics All these agents have easily measurable endpoints

Plasma concentration-no relation with effect : 

Plasma concentration-no relation with effect Drugs that act irreversibly & effects persist long after drug has left plasma. Such drugs destroy or inactivate enzyme, receptor & restoration occurs only after days or weeks when resynthesis takes place. Monoamine Oxidase Inhibitors (MAOIs) Cyclo-oxygenase inhibitor on platelets – Aspirin. Anticholinesterases Anticancer Drugs

Plasma concentration-poor correlation with effect : 

Plasma concentration-poor correlation with effect Inflammatory states-basic drugs like lidocaine show higher concentrations if total drug concentration is measured Assay method in use-failure to measure active metabolites eg BZD Hypersensitivity/idiosyncratic reaction

Other samples : 

Other samples USE OF SALIVA IN DRUG MONITORING: it is non invasive. Drug binding to salivary proteins may produce discrepancies. bind to oral cell debris. Salivary flow may be reduced Especially in children –serves as a easy ,safe and non invasive means

MAJOR CAUSES OF UNEXPECTED SERUMCONCENTRATION IN PATIENTS: : 

MAJOR CAUSES OF UNEXPECTED SERUMCONCENTRATION IN PATIENTS: non compliance inappropriate dosage malabsorption poor bioavailability drug interactions hepatic or renal disease altered protein binding genetic factors.

Timing of sample collection : 

Timing of sample collection Collect sample after steady state is attained (C ss ) ie after 4-5 half lives Peak concentration C ss max 1-2 hours after oral dose 4-6 hrs after sustained release 1 hr after IV dose Trough conentration C ss min 10-20 min after oral dose Immediately after IV Immediate sampling in case of toxicity

Slide 45: 

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 For all other drugs trough levels are taken

Sample timing for some important drugs : 

Sample timing for some important drugs a)Phenytoin:timing of concentration monitoring is not critical. b) Carbamazepine:trough concentration taken just after a dose. c) Digoxin:must be made atleast six hours after a dose. d) Theophylline:timing of sampling is not critical. e) Lithium:A 12 hr sample. f) Phenobarbitone: Any time sample is sufficient g) Gentamicin: Pre dose peak; 0.5 hr after i.v. and 1 hr after i.m. administration.

Source of errors : 

Source of errors Wrong patient/sample/timing Problem in drawing sample Transport and storage of sample Wrong estimation Interpretation of data lithium and aminoglycosides-blood samples should be allowed to clot and should be separated within 1 h. cyclosporine- important to consult the local laboratory for details on the proper sampling technique and post-dosage timing

Commonly monitored drugs : 

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

TDM for specific drugs : 

TDM for specific drugs Phenytoin Narrow therapeutic range-10-20 mg/l Dose dependant side effects Nystagmus,ataxia,confusion(20mg,30mg,40mg/l) Zero order kinetics Highly protein bound 90% Dose adjustment in renal failure Sample-C ss peak 2-4 weeks after initiating dose Dose increments must not be >25-50 mg/day

Digoxin : 

Digoxin Most commonly monitored drug. Sampling is often inappropriate. Target concentration ranges – 0.8-2 mg/L. Monitoring- borderline renal function aged subjects, patients with rapid atrial fibrillation who require higher digitalis doses for heart rate control

aminoglycosides : 

aminoglycosides 8hrly dosing regimen TCI-8 mg/l after first dose and an average concentration of 3 mg/l with maintenance dose Amikacin-peak-25 mg/l -Average-9mg/l Duration of therapy-5-7 days

lithium : 

lithium Lithium: narrow therapeutic index. Cleared renally TR-0.6-1.2 mmol/L Target -0.4mmol/L:sample taken 12 hrs after dose.

antidepressants : 

antidepressants Controversial use of TCI –depression is episodic Presence of active metabolites Concentration above optimum levels-negative influences on mood Metabolized by CYP 2D6 Amitriptyline plus nortryptyline100-250 mcg/l Nortryptline-50-150 mcg/l Imipramine plus desipramine-120-300mcg/l 3-4 weeks for steady states

cyclosporin : 

cyclosporin Used prophylactically-organ rejection Therapy in RA,psoriasis,bechets syndrome TC not well defined-vary between institutions Cardiac transplant recipients-500 mcg/l Renal transplant recepients-150 mcg/l Concentration determined of parent drug in whole blood(temperature dependant cellular uptake of drug)

Theophylline : 

Theophylline Cleared by hepatic metabolism. Effects demonstrated – target range 10-20 mg/l . Lower concentration associated with anti-inflammatory and steroid sparing effects.

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 > 5 umol/L duration of infusion 48 h > 0.5 umol/L 72 h > 0.05 umol/LImmunosuppressantsCyclosporine 3 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 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 > 5 umol/L duration of infusion 48 h > 0.5 umol/L 72 h > 0.05 umol/LImmunosuppressantsCyclosporine 3 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 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 : 

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

Drug Time to steady state Sampling time Therapeutic range (mg/L)AntiepilepticsCarbamazepine 2-6 d Trough 5-12Ethosuximide 1-2 wk Any time 50-100Phenobarbital 3 wk Any time 15-40Phenytoin 7 d 2-4 h 10-20 Valproate 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 : 

Drug Time to steady state Sampling time Therapeutic range (mg/L)AntiepilepticsCarbamazepine 2-6 d Trough 5-12Ethosuximide 1-2 wk Any time 50-100Phenobarbital 3 wk Any time 15-40Phenytoin 7 d 2-4 h 10-20 Valproate 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

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 : 

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

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

Slide 62: 

PATIENT CARE -Decrease duration of stay in hospital - Receive safer and more effective Rx - More economic - Increased productivity - Improve quality of life

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

FACTORS AFFECTING TDM : 

FACTORS AFFECTING TDM 1.alternative system of medicine-eg ayurvedic medication 2.Tropical disease and nutritional deficiencies-subclinical and known to alter drug PK 3.Ethnic differences and extrapolation-mostly derived from the west and may account for the PK differences 4.Quality control of drug assay-still not accredited in developing countries 5.Quality of medication and generic formulation-may require additional quality control

summary : 

summary combined approach important role in the development of safe and effective therapeutic medications and individualization of these medications to identify problems with medication compliance among noncompliant patient cases TDM purports to improve patient responses to important life-sustaining drugs and to decrease adverse drug reactions