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THERAPEUTIC DRUG MONITORING INTRODUCTION 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. It involves the use of drug concentration...

THERAPEUTIC DRUG MONITORING INTRODUCTION 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. It involves the use of drug concentration measurements in body fluids as an aid to the management of drug therapy for the cure, alleviation or prevention of disease. 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. CONCEPT OF THERAPEUTIC DRUG MONITORING (TDM) TDM is based on the principle that for some drugs there is a close relationship between the plasma level of the drug and its clinical effect. If such a relationship does not exit TDM is of little value. The clinical value of plasma level monitoring depends on how precisely the treatment outcome can be defined. STEPS INVOLVED IN TARGET CONCENTRAYION STRATEGY 1) Select a target concentration 2) Predict clearance and volume of distribution values for the patient based on population pharmacokinetic parameters and observable individual characteristics(weight, renal function) 3) Calculate the loading dose and maintenance dose rate to achieve the target concentration 4) Administer the doses and measure drug concentrations 5) Use the measured concentrations to predict individualized values of clearance and volume of distribution for the patient 6) If appropriate, revise the target concentration for the individual based on clinical assessment 7) Revert to step 3. TDM OF ESTABLISHED DRUGS 1. Cardio active drugs : Amiodarone, digoxin,digitoxin,disopyramide lignocaine,procainamide,propranolol and quinidine 2. Antibiotics : Gentamicin, amikacin and tobramycin 3. Antidepressants : Lithium and tricyclic antidepressants 4. Antiepileptic drugs : Phenytoin, phenobarbitone, benzodiazepines, carbamazepine, valproic acid and ethosuximide 5. Bronchodilators : Theophylline 6. Cancer chemotherapy : Methotrexate 7. Immunosuppressives : Cyclosporine, Tacrolimus TDM -INDICATIONS ❖ Drugs with a narrow therapeutic window:- will allow dosage alterations to produce optimal therapeutic effect or to avoid toxic effects. Ex: Lithium, phenytoin, and digoxin ❖ Drugs for which there is difficulty in measuring or interpreting the clinical evidence of therapeutic or toxic effects:- Nausea & vomiting occur in both digitalis toxicity & congestive heart failure. TDM -INDICATIONS ❖ Renal disease: Alter the relationship between dose & the plasma concentration. Important in case of digoxin, lithium & aminoglycoside antibiotics. ❖ Drug interactions: When another drug alters the relationship between dose & plasma concentration e.g. plasma concentration of lithium is increased by thiazide. ❖ For diagnosis of suspected toxicity & determining drug abuse ❖ To evaluate compliance of patient ❖ Guiding withdrawal of therapy: Antiepileptics, Cyclosporine. DRUGS THAT ARE NOT SUITABLE FOR TDM 1) Drugs having wide therapeutic index 2) Toxicity is not a realistic concern (Penicillin) 3) Effects can be measured using functional laboratory tests (Anticoagulants) 4) Plasma concentration not predictably related to effects (Anticoagulants) 5) Effect of the relationship remains undefined (Antidepressants) 6) Hit and run drugs: Omeprazole, MAO inhibitors BASIC PRINCIPLES OF THERAPEUTIC DRUG MONITORING The following are important considerations to ensure an optimum TDM service in any setting: (1)Measurement of patient’s serum or plasma drug concentration taken at appropriate time after drug administration (2) Knowledge of pharmacological and pharmacokinetic profiles of the administered drugs (3)Knowledge of relevant patient’s profile like demographic data, clinical status, laboratory and other clinical investigations, and (4)Interpretation of SDC after taking into consideration all of the above information and individualizing drug regimen according to the clinical needs of the patient. PROCESS OF TDM 1) 2) 3) 4) Development of plasma profile in each patient Administering a predetermined dose of drug Collection of blood samples Determination of blood samples Plasma profile and pharmacokinetic model development: – Clinical effect of drug – Development of dosage regimen – Diagnosis, dosage form selection, dosage regimen, initiation of therapy EVALUATION OF CLINICAL RESPONSE SAMPLES Sample selection must include an appropriate matrix. Plasma or serum is commonly used for drug assays. Whole blood:- for Cyclosporine, tacrolimus, sirolimus, as there are large shifts of drug between red cells and plasma with storage and temperature change. Saliva, which gives a measure of the unbound drug concentration, may be a useful alternative when blood samples are difficult to collect. Ex: Phenytoin ,Lithium, Amitryptyline Before collecting the sample: Establish that SDC is at steady-state Ensure complete absorption and distribution TIMING OF SAMPLE COLLECTION A trough level is drawn immediately before the next dose of the drug is administered. A peak level is drawn 1 to several hours after the drug is administered (depending on the drug). The best sampling time is in the predose or trough phase. Peak concentration may be useful for some antibiotics: Aminoglycosides MAJOR SOURCES OF PHARMACOKINETIC VARIABILITY Patient Compliance Age – neonates, children, elderly Physiology – gender, pregnancy Disease – hepatic, renal, cardiovascular, respiratory Drug-to-drug interactions PHARMACOKINETIC PARAMETERS Five pharmacokinetic parameters that are important in therapeutic drug monitoring include: i. Bioavailability. ii. Volume of distribution and distribution phases. iii. Clearance iv. Half-life v. Protein binding of drugs. CLINICAL SIGNIFICANCE OF TDM 1. Maximizes efficacy 2. Avoids toxicity 3. Identifies therapeutic failure – Non compliance, subtherapeutic dose 4. Facilitates adjustment of dosage 5.Facilitates the therapeutic effect of drug by achieving target drug concentration 6. Identify poisoning, drug toxicity and drug abuse