Immunology and immunodiagnostics Lecture 8

TDM Therapeutic drug monitoring is the measurement of specific drugs at timed intervals in order to maintain a relatively constant concentration of the medication in the bloodstream. To provide information relevant to the diagnosis and management of the patients suspected to have taken overdose. To screen for the presence of drug of abuse.

Need of TDM Certain drugs have a narrow therapeutic range In concentrations above the upper limit of the range,the drug can be toxic. In concentrations below the lower limit of the range,the drug can be ineffective. Not all patients have the same response at similar doses.

Drugs should have a narrow "therapeutic index” Steady state varies from person to person and depends on Age General state of health Genetic makeup interference of other medications Various disease states

Therapeutic index a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies).

Therapeutic Index High therapeutic index Low therapeutic index NSAIDs Aspirin Tylenol Ibuprofen Sedative/hypnotics Benzodiazepines Most antibiotics Beta-blockers Low therapeutic index Lithium Neuroleptics Phenytoin Phenobarbital Some antibiotics Gent/Vanco/Amikacin Digoxin Immunosuppressives

DO ALL DRUGS NEED TDM? Drugs that do not need TDM: Drugs used for treating diseases with having end point BP, HR, cardiac rhythm, blood sugar, blood cholesterol and triglycerides, urine volume, body temperature, inflammation, pain, headache, etc. Drugs with less complicated pharmacokinetics. Drugs that used to treat less complicated or not life threatening diseases

COMMONLY MONITORED DRUGS 1. Bronchodilators: Theophylline 2. Antibiotics : Aminoglycosides - Gentamicin, Amikacin Others - Vancomycin 3. Immunosuppressants: Cyclosporine 4. Anticancers: Methotrexate

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

TDM ASSAY METHODOLOGIES 1. EMIT (Enzyme-Multiplied Immunoassay Technique) : highly automated, rapid turnaround, many assays available, homogenous, moderate sensitivity 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) 4. FPIA (Fluorescence Polarization Immunoassay) 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 Total drug conc. Free drug conc. Metabolites

Theophylline Bronchodilator Therapeutic range: 5 - 20 g/mL Neonates metabolize theophylline to caffeine Toxic at > 20 g/mL Nausea, vomiting, diarrhea, stomach pain, headache, insomnia, tachycardia Seizures, cardiac arrhythmia at > 35 g/mL

Gentamycin/Tobramycin Wide-spectrum aminoglycoside antibiotics Therapeutic 4 - 10 g/mL (peak); 0.5 - 1.5 g/mL (trough) Toxic: 12 - 15 g/mL Ototoxicity Nephrotoxicity

Digoxin Improves cardiac output in CHF patients Therapeutic range: 1.5 - 2.0 ng/mL Toxic levels (> 2.0 ng/mL) produce arrhythmias, GI, CNS symptoms