THERAPEUTIC DRUG MONITORING (TDM)

MUHAMMAD UMAIR KHAN

B.Pharm (UoK); MSc Pharmacotherapy (UK)

Definition

Individualization of drug doses by maintaining plasma/blood drug concentrations within a target rangetherapeutic range.therapeutic window.

Therapeutic Window Therapeutic failure results when either the concentration is too low, ineffective therapy, or is too high, producing unacceptable toxicity. Between these limits of concentration lies a region associated with therapeutic success regarded as a Therapeutic window.

Concept of TDM
Prescribed dosing regimen
Drug at site of action or blood concentration Clinical effects or drug effects

Pharmacokinetic variability 1. Compliance 2. Dosing or medication errors 3. Tissue and body fluid volume 4. Drug interactions

Pharmacodynamic variability 1. Drug receptor status 2. Genetic factors 3. Drug interactions 4. Tolerance

DO ALL DRUGS NEED TDM ????

Drugs Which Needs TDM TDM is useful in drugs:

With a narrow therapeutic index Which are highly protein-bound

Which are liable to interact

In which the metabolite might be toxic

Benefits
It is also useful in cases where:

The usual dose of a drug does not produce expected results

Clinical benefit is related to serum drug concentrations but is

difficult to assess Clinical signs of toxicity may be difficult to recognize Social habits may affect the handling of a drug (e.g. smoking, alcohol)

Patients have other co-morbidities which can alter

pharmacokinetic parameters (e.g. Renal failure, Hepatic failure)

Drugs Suitable for TDM

Drug Category
Cardiac drugs

Drugs

Treatment Use

Digoxin, digitoxin, Congestive heart failure, quinidine, procainamide, Nangina, arrhythmias acetyl-procainamide Aminoglycosides (gentamicin, tobramycin, Infections with bacteria that are resistant to less toxic

Antibiotics

amikacin), Vancomycin,
Chloramphenicol Antiepileptics Phenobarbital, phenytoin, valproic acid, carbamazepine

antibiotics

Epilepsy, prevention of seizures, sometimes to stabilize moods

Continued..
Bronchodilators Theophylline, caffeine Asthma, COPD, neonatal apnea Anti-cancer drugs Methotrexate Rheumatoid arthritis, various cancers, nonhodgkin's lymphomas Prevent rejection of transplanted organs,

Immunosuppressants

Cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine

autoimmune disorders

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 serum SDC and therapeutic/toxic effects

CRITERIA FOR TDM (contd)

6. Lack of therapeutic effects is dangerous 7. Difficulty in interpreting signs and symptoms of toxicity or therapeutic failure or in evaluating therapeutic responses : Toxicity vs therapeutic failure : Therapeutic responses

Sampling
Proper selection of Sample time is of vital importance in obtaining an effective TDM. Generally biological samples (mostly venous blood) are collected after the drug reaches steady state concentration. For most of the drugs, Steady-state concentration is reached at least after 5 biological half lives.

 The point in dosing interval which is least inconsistent is known as pre-dose or trough concentration. The dosing interval and duration of dosing are the factors which influence variations in drug concentrations in plasma

The Sample Request Form

Timing of Sample Collection

The timing of blood collection -- important part of TDM When a person takes a dose of a drug, the amount in the blood rises for a time period, peaks, and then begins to fall, usually reaching its lowest level (trough) just before the next dose. By experience and studies, doctors know when to expect peaks and troughs to occur and will request blood sample collections as either trough levels (usually drawn just before the next dose), peak levels (timing varies depending on the drug), or sometimes will request a random level. The best sampling time is in the predose or through phase just prior to a maintenance dose, when a drug is administered by multiple oral doses.

Analytical Methods Used for TDM:

The analytical methodology employed in TDM should ideally: 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

Methods commonly used in TDM are:

Spectrophotometry and Fluorimetry Thin layer chromatography (TLC) HPLC and GLC Radio immuno assay (RIA) Enzyme Immuno assay Fluorescence polarization Immunoassay (FPIA)

Clinical interpretation of results

Clinical conditions requiring TDM for drugs used for prophylaxis
Collection of biological sample Transfer to laboratory and estimation of drug concentration by suitable method Interpretation of TDM results with reference to clinical conditions Inadequate/Lack of Clinical response Below TR
Check the follow up of therapy

Satisfactory Clinical response

Above TR

Within TR
Check the follow up of therapy

Below TR
Other possible reasons for signs of toxicity should be considered. Laboratory errors should be checked

Within TR
Other possible reasons for signs of toxicity should be considered. Lower dose can be given if result indicates the relief of disease

Above TR
Discontinue the therapy and restart with a low dose

Change or re consider drug therapy

Increase dose if required

If required a small change in dose should be considered

Role of Pharmacist in TDM:

A clinical pharmacist may assist other health care professionals by advising them about correct use if TDM- sampling time, sampling technique and interpretation of results. They also may be engaged in: 1. Selecting initial drug dosage regimen-dose, dosing interval, route of administration, dosage form.

1. Depending upon the TDM results and patients response, revision and adjustment of dosage regimen should be done. 2. Assessing various other reasons for unexpected results like patients non-compliance, medication or laboratory errors, DDIs etc. 3. Evaluating and adjusting dosage for patients on haemodialysis. 4. Managing acute drug interactions.

Limitations
Scientific accuracy of drug assays Laboratory variability in reporting Validity of suggested target ranges. Active metabolites which contribute to the therapeutic response cannot be measured.

Problems In Implementation
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 patients history and other necessary data No consultation when problems arise

Clinical Usefulness of TDM

Maximizing Efficacy - Epileptic pt. vs Phenytoin - Burn pt. vs Gentamicin - Asthmatic pt. vs Theophylline - Life-saving in serious situations

cont
Avoiding Toxicity - Overdose - Differentiate adverse effects from disease states : Digoxin toxicity vs ventricular arrhythmias : Digoxin toxicity vs hypo-K or hyper-Ca - Altered pharmacokinetics

cont.

Identifying Therapeutic Failure - Non-compliance - Subtherapeutic dose - Bioavailability problem - Malabsorption - Drug interactions

cont

Facilitating Therapeutic Effects - Target drug conc.: Antiepileptics - Dosage adjustment

Cost-Benifits of TDM
Hospital Perspective - Reduce hospital congestion - Increase quality of Rx and service - Economic consideration - Personnel: research, promotion & self esteem - Medico-legal aspects

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