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WHAT IS TDM ?
TDM refers to the individualization of dosage by maintaining plasma or blood drug concentration within a target range (therapeutic range).
Goal of TDM is to achieve a desired beneficial effect with minimal adverse effects.
Therapeutic Index
High therapeutic index
NSAIDs
Aspirin Tylenol Ibuprofen
Sedative/hypnotics
Benzodiazepines
Some antibiotics
Gent/Vanco/Amikacin
Digoxin Immunosuppressives
Therapeutic Index
Sub-therapeutic
Toxicity
Toxic
WHY TDM ?
1. Each person will have ADME at different rates based on their a) age,weight, gender, b) genetic makeup, c) diseased conditions.
2. Useful in maintaining drug concentration within the therapeutic range which are taken for lifetime, and reduces toxic effects.
WHY TDM ?
3. Identify patient noncompliance, decrease in the efficiency of and dysfunctions in the body metabolism and elimination of drug.
Purpose of TDM
To confirm effective concentrations To investigate unexpected lack of efficacy To check compliance To avoid or anticipate toxic concentrations Before increasing to unusually large doses Limited role in toxicology - drug screen
1. 2. 3. 4. 5. 6. 7.
Low therapeutic index, Poorly defined clinical end point, Therapeutic failure, Drugs with saturable metabolism, Wide variation in the metabolism of drug, Major organ failure, Prevention of adverse effects of life time drugs.
TDM OF ESTABLISHED DRUGS:1. Cardio active drugs : amiodarone, digoxin, digitoxin disopyramide, lignocaine, procainamide, propranolol and quinidine 2. Antibiotics : gentamycin, 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
Development of plasma profile in each patient 1)administering a predetermined dose of drug 2)Collection of blood samples 3)Determination of blood samples in each sample 4)plasma profile and pharmacokinetic model development Clinical effect of drug Development of dosage regimen Diagnosis, dosage form selection, dosage regimen ,initiation of therapy and evaluation of clinical response
Process of TDM
Pharmacokinetic Considerations
Is the aim to provide constant concentrations? - eg anticonvulsants Is the aim to achieve transient high concentrations without toxicity? - eg gentamicin Are drug concentrations likely to vary greatly between individuals on the same dose? - eg phenytoin Remember it takes around 5 half-lives to reach steady state
Practical considerations
Can the lab actually measure the drug? What sample is needed? What is the right timing? Is there an accepted therapeutic range
MEC - threshold concentration above which efficacy is expected in most patients with the disorder MTC - upper concentration above which the rate and severity of adverse effects become unacceptable
Samples?
plasma or serum is used for drug assays whole blood:- cyclosporin, tacrolimus, sirolimus there are large shifts of drug between red cells and plasma with storage and temperature change so whole blood is assayed saliva, which gives a measure of the unbound drug concentration, may be a useful alternative when blood samples are difficult to collect. phenytoin ,Lithium, amitryptyline
Conc(ug/l)
Trough Conc
Time (hours)
ANALYTICAL METHODOLOGY:The analytical methodology employed should ideally: 1. Distinguish between drug and its metabolites, 2. Detect small amounts, 3. Specificity 4. Unaffected by other drugs administered,and 5. Should be accurate, precise, linearity.
ANALYTICAL METHODOLOGY
Commonly used analytical methods are: 1. 2. 3. 4. 5. 6. Spectrophotometry and fluorimetry, Thin layer chromatography, HPLC and GLC, Radio immuno assay(RIA) Enzyme immuno assay(EIA) Fluorescence ploarization immunoassy(FPIA)
For therapeutic drug monitoring the information required to allow interpretation of the result should include:1. the time of the sample collection, 2. the time of the last dose, 3. the dosage regimen and 4. the indication for drug monitoring.
The drug concentration in the collected samples are measured, and the other data such as high serum creatinine and high blood urea nitrogen levels are also measured to check the kidney function.
Patient non compliance Error in dosage regimen, Rapid elimination, Timing of sample changing hepatic blood flow Poor bioavailability. Reduced plasma binding.
Error in dosage regimen Rapid bioavailability, Slow elimination, Increased plasma protein binding Decreased renal/hepatic function
Serum concentration correct but patient does not respond to therapy Altered receptor sensitivity(tolerance) Drug interaction at receptor site
Pharmacokinetic software are available for dose calculation of drug with narrow therapeutic window DATAKINETICS ABBOTTBASE PHARMACOKINETIC SYSTEM The dosage regimen is calculated by using the NOMOGRAM by considering the age, body weight, and physiological state of the patient.
TDM - examples
Lithium - used for bipolar disorder Toxic - neurological, cardiac, renal Narrow therapeutic range:
0.8 - 1.2 mmol/L acutely 0.5 - 0.75 mmol/L for maintenance Chronic concentrations of 3.0 are potentially lethal
Anticonvulsants
Variable dose dependant kinetics Most metabolised through cytochrome P450 system Concentration-related CNS toxicity can be partly avoided by TDM However severe skin rashes, liver and marrow toxicity cannot be predicted or avoided With phenytoin small dose increases can produce disproportionate rises in blood levels and toxicity Sometimes free (unbound) concentrations need to be measured - eg hypoalbuminaemia, pregnancy
Digoxin
Has variable bioavailability Has variable clearance (by kidney) - remember the elderly Drug interactions are fairly common Relationship between concentration and effect is not constant - concentrations soon after dosing are difficult to interpret. Range is approx 1 to 2 nmol/L Patients may become more sensitive to a given concentration - eg hypokalalaemia, hypothyroidism In atrial fibrillation titrate against the ventricular rate Concentrations should be measure at least 6-8 hours after the last dose
Cyclosporin
Used as immunosuppressant in transplant rejection Low therapeutic index and toxicity (kidney) is severe Interactions are common - eg calcium channel antagonists Plasma range 50-300 mg/L
Theophylline
Declining use in asthma Very narrow therapeutic index: 55 - 110 umol/L (should be lower) At the high end toxicity is common Toxicity is severe - GI, neuro, cardiac Interactions are common - erythromycin, cyclosporin, cimetidine, smoking
Gentamicin
Practice is changing - trend to once/daily dosing Toxicity relates to trough concentrations, particularly with prolonged therapy Desirable range:
peak 6 - 10 mg/L trough 1-2 mg/L