Therapeutic Drug Monitoring

Hi!Friends

Therapeutic drug monitoring is a branch of clinical chemistry that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrowtherapeutic range, i.e. drugs that can easily be under- or overdosed.

WHY TDM REQUIRED

Therapeutic drug monitoring is the measurement of specific drugs at intervals in order to maintain a relatively constant concentration of the medication in the bloodstream. Drugs that are monitored tend to

Ø  Low therapeutic index

Ø  Poorly defined clinical end point

Ø  Non compliance

Ø  Therapeutic failure

Ø  Drugs with saturable metabolism

Ø  Wide variation in the metabolism of drugs

Ø  Major organ failure

Ø  Drugs taken for a lifetime.

Ø  Prevention of adverse drug effects

They must be maintained at steady concentrations year after year while the patient ages and goes through life events such as pregnancies, temporary illnesses, infections, emotional and physical stresses, accidents, and surgeries. Over time, patients may acquire other chronic conditions that also require lifetime medication and that may affect the processing of their monitored drugs. Examples of these conditions include cardiovascular disease, kidney disease,thyroid disease, liver disease, and HIV/AIDS
For which drugs is monitoring helpful?
The characteristics of drugs which make them suitable for, or make them require, therapeutic drug monitoring are: 

Ø  Marked pharmacokinetic variability

Ø  Concentration related therapeutic and adverse effects

Ø  Narrow therapeutic index

Ø  Defined therapeutic (target) concentration range

Ø  Desired therapeutic effect difficult to monitor

Monitoring can help identify decreases in the efficiency of and dysfunctions in the body in metabolizing and eliminating therapeutic drugs.

SPECIFICITY

 Each person will absorb, metabolize, utilize, and eliminate drugs at a different rate based upon their

Ø  Age,

Ø  General state of health,

Ø  Genetic makeup, and

Ø  The interference of other medications that they are taking.

Therapeutic drug monitoring follows these changes and accommodates them. It identifies patient noncompliance (when the patient does not take the medication regularly as prescribed), identifies the effect of drug interactions (may cause drug concentrations that are higher or lower than expected at a given dosage), and helps to tailor dosages to fit the current needs of the specific patient.

Therapeutically monitored drugs 

There are several categories of drugs that require monitoring, as summarized in the table below. 

Drug Category	Representative	Treatment Use
Cardiac drugs	Digoxin, digitoxin, quinidine, procainamide, N-acetyl-procainamide (a metabolite of procainamide)	Congestive heart failure, angina,arrhythmias
Antibiotics	Aminoglycosides (gentamicin, tobramycin, amikacin)Vancomycin, Chloramphenicol	Infections with bacteria that are resistant to less toxic antibiotics
Antiepileptics	Phenobarbital,phenytoin, valproic acid, carbamazepine, ethosuximide, sometimes gabapentin, lamotrigine	Epilepsy, prevention of seizures, sometimes to stabilize moods
Bronchodilators	Theophylline, caffeine	Asthma, Chronic obstructivepulmonary disorder (COPD),neonatal apnea
Immunosuppressants	Cyclosporine,tacrolimus, sirolimus,mycophenolate mofetil, azathioprine	Prevent rejection of transplanted organs,autoimmune disorders
Anti-cancer drugs	Methotrexate	Psoriasis,rheumatoid arthritis, various cancers, non-hodgkin's lymphomas, osteosarcoma
Psychiatric drugs	Lithium, valproic acid, some antidepressants (imipramine, amitriptyline, nortriptyline, doxepin, desipramine)	Bipolar disorder (manic depression), depression
Protease inhibitors	Indinavir, ritonavir, lopinavir, saquinavir, atazanavir, nelfinavir	HIV/AIDS

Approach used in TDM

Through years of testing, the optimum therapeutic blood level range for each drug has been determined. In this range, most people will be effectively treated without excessive side effects or symptoms of toxicity. The drug dosage to reach this level must be individually determined. When a patient starts on a monitored drug (or returns to it after an absence), the doctor adjusts the dose upwards and tests blood concentrations frequently until the appropriate steady state level is achieved. If a patient’s levels are too high, the doctor will adjust them lower. Often, each different dosage level will take a short period of time to stabilize so these corrections up and down may take place over a few days or weeks (although if they are causing symptoms associated with toxicity, they will be decreased relatively rapidly to relieve these symptoms). It is important that patients work closely with their doctors during this process and not make their own adjustments or stop taking their medication. Abrupt changes can sometimes worsen conditions and cause acute symptoms.

If treatment is effective

Once the patient’s results are in the therapeutic range and their clinical signs indicate that the treatment is appropriate, then the doctor may monitor the drug at regular intervals and as needed to accommodate changes in patient status to ensure that the drug stays in the therapeutic range. The frequency of testing required will depend on the drug and on the needs of the patient.

If treatment is ineffective

If treatment does not appear to be fully effective or if the patient has either excessive side effects or signs of toxicity, then testing will be done to see if blood concentrations have become too low or high. If they have, then the dosage will be adjusted; if they have not, then the patient and doctor may need to re-evaluate the use of that specific medication and consider switching to another type of drug if it is available.

Sampling And Drug Analysis
Drug assay methods should have adequate sensitivity, be specific for the drug (or metabolite) to be measured and have appropriate accuracy and precision. Most high-volume drug assays are now carried out by automated immunoassay methods which have these characteristics. However, a number continue to require manual assay by methods such as high performance liquid chromatography (HPLC) and gas liquid chromatography (GLC) (e.g. amiodarone, perhexiline). National and international quality control programs are available for most commonly monitored drugs, and reputable laboratories are accredited by organisations such as the National Association of Testing Authorities.

Information required before TDM

Ø  Time of sample in relation to last dose

Ø  Duration of treatment with the current dose

Ø  Dosing schedule

Ø  Age, gender

Ø  Other drug therapy

Ø  Relevant disease states

Ø  Reason for request e.g. lack of effect, routine monitoring, suspected toxicity.

Procedures to adopt in TDM

There are three procedures to be followed while doing TDM

1.      The effect of a drug may be monitored by its clinical effect e.g. lowering of blood-pressure, the prophylaxis of migraines or the reduction in inflammation by steroids.

2.      The biological effect of the drug may be followed by its biochemical effects eg glucose modulation by insulin, reduction in CRP or plasma viscosity with anti-inflammatory agents, the lowering of uric acid with allopurinol or increase in prothrombin time by warfarin.

3.      A small number of therapeutic agents may be usefully monitored by their plasma concentrations. These measurements are only of value if the plasma values reflect the biological/therapeutic effect of the drug. This value is illustrated particularly well by digoxin and phenytoin both of which have side effects that are similar to the conditions which they are used to treat (phenytoin toxicity may produce fits and digoxin toxicity may produce cardiac dysrhythmias). The measurement of other drugs such as lithium and theophylline is useful as the concentrations reflect both under- or over-therapy and also correlate with toxic biological effects.

Useful Points

Ø  If patients take their digoxin or lithium tablets in the evening or at midday, then all samples taken in a morning surgery will be taken at the correct time.

Ø  Digoxin toxicity is potentiated by hypothyroidism and low concentrations of potassium.

Sampling time

In general, the specimen should be drawn after steady state is reached (at least 4 half-lives after a dosage adjustment) and just before the next dose (trough level).
Peak and trough levels may be indicated to evaluate the dosage of drugs whose half-lives are much shorter than the dosing interval. Example: Gentamicin.

                                    


Information required for interpretation 
Drug concentrations need to be interpreted in the context of the individual patient without rigid adherence to a therapeutic range.
There are two important factors which can make interpretation of a result difficult in some cases. These are 

Ø  changes in protein binding

Ø  active metabolites.

MAJOR CAUSES OF UNEXPECTED SERUM CONCENTRATION IN PATIENTS:

The most important causes of unexpected serum concentrations are non compliance, inappropriate dosage, malabsorption, poor bioavailability, drug interactions, hepatic or renal disease altered protein binding and genetic factors. If these factors can not be eliminated, a dosage adjustment is required. For drugs with linear kinetics the following formulae may be used:

Desired drug concentration

                            

                         New dose = Old dose X Old drug concentration

Pharmacodynamic uses

If the clinical effect can be readily measured (e.g. heart rate, blood pressure), it is obviously better to adjust the dose on the basis of response. Where this cannot be done, therapeutic drug monitoring is used in two major situations:

Ø   Drugs used prophylactically to maintain the absence of a condition such as seizures, cardiac arrhythmias, depressive or manic episodes, asthma relapses or organ rejection

Ø  To avoid serious toxicity as with the aminoglycoside antibiotics which, unlike most antibiotics, have a narrow therapeutic range.

Ø  Most drugs' responses are graded responses and are continuous through the concentration range Therapeutic responses do not magically 'switch on' at the lower limit of the therapeutic range nor do toxic responses suddenly appear at the upper limit.

Ø  Individual patients will have individual therapeutic ranges - this is the residual pharmacodynamic variability

Sampling And Drug Analysis

Drug assay methods should have adequate sensitivity, be specific for the drug (or metabolite) to be measured and have appropriate accuracy and precision. Most high-volume drug assays are now carried out by automated immunoassay methods which have these characteristics. However, a number continue to require manual assay by methods such as high performance liquid chromatography (HPLC) and gas liquid chromatography (GLC) (e.g. amiodarone, perhexiline). National and international quality control programs are available for most commonly monitored drugs, and reputable laboratories are accredited by organisations such as the National Association of Testing Authorities.

ANALYTICAL METHODOLOGY:

The methods currently available for analyzing data obtained in drug disposition studies are enormous. The fundamental procedures necessary for the quantification of the drug in the body are:

Ø  Recovery from body fluids,

Ø  Tissues, and organs,

Ø  Separation from the biological components,

Ø  Identification of the species concerned and finally quantification.

The analytical methodology employed should ideally:

Ø  Distinguish between compounds of similar structure unchanged drug and metabolites.

Ø  Detect small amounts

Ø  Be simple enough to use as a routine assay

Ø  Be unaffected by other drugs administered simultaneously.

1          Spectrophotometry and Fluorimetry:

Prior to advent of GLC and HPLC, drug samples were analyzed by spectrophotometric methods. Solvent extraction schemes coupled with a spectrophotometric finish can still provide a much derived simplicity in assay procedure when the level of sensitivity required is not too low. i.e. in the ug/ ml range.

Drawbacks

Ø  Large volume of samples,

Ø  complex extraction procedures

Ø  interference by other compounds.

2.             Thin layer chromatography (TLC):

TLC possess adequate resolutions for identifying many drugs but it suffers from inability to quantify these drugs accurately and time consuming technique with inadequate sensitivity. However it is a useful techniques in toxicology laboratory.

3.         HPLC and GLS:

These methods are highly specific, precise and sensitive. Besides multiple analyses can be done.

Drawbacks

Ø  Extraction step required

Ø  Slow, single serial analysis,

Ø  Column degenerates with time and

Ø  Complex analyses require considerable processing.

Out of these two, HPLC technique is superior because thermo labile compounds can also be analyzed.

4.            Radio immuno assay (RIA):

It is sensitive, reasonably precise but requires the use of radionucleides. Cross reactivity with other closely reacted drugs is a potential problem with this technique. Besides it is not possible to find out the optically active isomer. The hazards of using 24 radioactive material is a considerable limitation of this method.

5.            Enzyme Immuno assay:

These techniques offer some advantages over RIA in that no radioactive tracer is required; there is no need to separate the bound from the unbound fractions. However the potential for cross reactivity still exits. Burgess et al3 compared serum phenytoin concentration in patients with normal renal functions and in patients with end stage renal disease using EMIT and GLC and found that patients with renal insufficiency and EMIT values were 90% higher than GLC values, Digoxin RIA remains as one of the most precise and sensitive methods for quantitation of digoxin in patients serum.

6.         Fluorescence polarization Immunoassay

This assay procedure combines competitive protein binding with fluorescence polarization to give direct measurement without the need for a separation procedure. The advantages of this method are accuracy, precision and short turn around time.

USE OF SALIVA IN DRUG MONITORING:

The concentration of a drug in saliva is proportional to the concentration of the unbound rather than to the total of bound and unbound drugs in plasma. The practice of measuring drugs in saliva is appealing because it is non invasive. However it has its limitations viz., some substances such as lithium are actively secreted into the saliva rather than by passive process. Drug binding to salivary proteins may produce discrepancies in plasma/salivary ratios, e.g. phenytoin. Drugs may also bind to oral cell debris, e.g. propranolol,  Salivary flow may be reduced in patients taking anti cholinergic drugs. Preparations used to stimulate salivary flow might interfere with drug estimation e.g. lemon flavored sweets interfere with

amitryptyline estimations.

Factors effecting TDM

EFFECT OF AGE:

Variability in response to drugs occurs at extremes of age. Elderly patients are more

sensitive to the CNS depressant effect of drugs but are less sensitive to cardiovascular effects of propranolol. On the other hand young children are more sensitive to CNS depression effects of morphine. However more data are needed on the effects of age on pharmacokinetic and pharmacodynamics of drugs to allow optional individualization of dosage.

PREGNANCY:

Little has ben published on the monitoring of mplasma drug levels during pregnancy. Plasma drug levels of phenytoin and phenobarbitone tend to reduce during pregnancy.

COST EFFECTIVENESS:

The measurement of drug levels in body fluidsmust be cost effective. The cost of performing an individual test is determined by the summing equipment, personnel, supply and overhead expenditure for a given period of time and dividing that amount but the number of assays performed in the same time interval. The fee charges is then determined by the test’s cost plus desired profit.The foregoing calculations produce an unreasonably expensive fee although high fee for unique tests requiring special methods may not be unreasonable. Cost-benefit analysis of gentamicin dosage regimens of burn patients with gram 26 negative septicaemia showed that a cost benefit ratio of 8.7 to 1.10 with decreased mortality and increased economic productivity. Use of clinical pharmacokinetics by therapeutic drug monitoring service offered substantial benefits like fewer adverse reactions, shorter intensive care unit stay and shorter overall hospital stay.

TDM will be useful if the following criteria are met:

Ø  The drug in question has a narrow therapeutic range,

Ø  A direct relationship exists between the drug or drug metabolite levels in plasma and     the pharmacological or toxic effects,

Ø  The therapeutic effect can not be readily assessed by the clinical observation,

Ø  Large individual variability in steady state plasma concentration exits at any given dose

Ø  Appropriate analytic techniques are available to determine the drug and metabolite levels.

TDM is unnecessary when

Ø  Clinical outcome is unrelated either to dose or to plasma concentration

Ø  Dosage need not be individualized

Ø  The pharmacological effects can be clinically quantified

Ø  When concentration effect relationship remains unestablished,

Ø  Drugs with wide therapeutic range such as beta blockers and calcium channel blockers.

Situation in which drug monitoring may not be useful

Ø  Drugs that can be given in extremely high doses before toxicity is apparent are not candidates for monitoring. Example: Penicillin.

Ø  If there are better means of assessing drug effects, drug level monitoring may not be appropriate. Example: Warfarin is monitored by measuring INR, not by serum levels.

Ø  Drug level monitoring to assess compliance is unreliable, since poor compliance cannot be distinguished from rapid metabolism without direct inpatient scrutiny of drug administration.

Ø  Drug toxicity is a clinical diagnosis. Drug concentrations within the usual therapeutic range do not rule out drug toxicity in a given patient. Example: Digoxin, where other physiologic variables (eg, hypokalemia) affect drug toxicity.

Ø  In summary, therapeutic drug monitoring may be useful to guide dosage adjustment of certain drugs in certain patients. Patient compliance is essential if drug monitoring data are to be correctly interpreted.

Points to be considered

DOSAGE REGIMEN:

It is one of the factors to be considered while interpreting TDM data. It is important to know the duration of drug therapy, dosage and when the last dosage was taken.

ACTIVE METABOLITE:

Many drugs are biotransformed into compounds that are pharmacologically active.

When evaluating the therapeutic effect of such drugs, the relative contributions of all active substances present in the serum must be integrated e.g. imipramine is biotransformed to the active metabolite – desipramine.

EFFECT OF DISEASE STATES:

Acute or chronic disease alters drug clearance patterns. Thus drug concentrations may be elevated or depressed depending on the pathophysiology of the system involved, e.g., liver disease impairs the clearance of drugs dependent upon conversion to more water soluble compounds. Congestive cardiac failure can precipitate elevated drug levels of agents dependent on hepatic metabolism for clearance

CLINICAL USEFULNESS OF TDM:

Ø  TDM data provides the clinician with greater insight into the factors determining the patients response to drug therapy. For example when a patient fails to respond to a usual therapeutic dose, measurement of plasma level can help to distinguish a noncompliant patient and a patient who is a true non-responder.

Ø  TDM also provides useful information regarding individual variations in drug utilization patterns and alteration in drug utilization as a consequence of altered physiological state or disease process.

Ø  TDM is a useful adjunct in treating many patients provided the potential pit falls and problems are considered.

Frequently Asked Questions

1. How does the doctor determine how much drug to give me?
There are many factors to consider. Some of them are your weight, body composition, age, temperature, nutrition, renal, liver, and heart conditions, burns, shock, and trauma. Your doctor takes these into account when prescribing a dosage quantity and frequency and then tailors your medication based upon the results of therapeutic monitoring.
2. What should I do if I forget to take my medication on time? 
Do not double your dose the next time. Consult your doctor or pharmacist to find out what you should do.
3. Can I monitor myself at home? 
No. Blood must be collected at specific times and tests must be performed using special laboratory equipment.