Various studies have shown that therapy guided by drug blood levels (therapeutic drug monitoring, TDM) has a considerably better chance of achieving therapeutic effect and preventing toxicity than therapy using empiric drug dosage. TDM can be helpful in a variety of circumstances, as can be seen in the following discussion.
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Why obtain therapeutic drug blood levels?

1. To be certain that adequate blood concentrations are reached. This is especially important when therapeutic effect must be achieved immediately but therapeutic results are not evident immediately, as might happen when aminoglycoside antibiotics are used.
2. When effective blood levels are close to toxic levels (“narrow therapeutic window”). It is useful to know what margin of safety is permitted by the current medication dose. If blood levels are close to toxic values, a decrease in the dose might be attempted.
3. If expected therapeutic effect is not achieved with standard dosage. It is important to know whether the fault is due to insufficient blood levels or is attributable to some other factor (e.g., patient tolerance to the medication effect or interference with the therapeutic effect by other drugs).
4. If symptoms of toxicity appear with standard dosage. The problem might be one of excessive blood levels, enhancement of effect by other medications, an increase in free as opposed to total drug blood levels, or symptoms that are not due to toxicity from the drug in question.
5. If a disease is present that is known to affect drug absorption, protein binding, metabolism, or excretion.
6. Possible drug interaction. It is safer to know in advance whether other medications have altered the expected blood levels of a drug before symptoms appear of toxicity or of insufficient therapeutic effect.
7. Combination drug therapy. If multiple drugs are used simultaneously for the same purpose (e.g., control of convulsions), knowledge of baseline blood levels for each drug would be helpful should problems develop and the question arise as to which drug is responsible.
8. Possible patient noncompliance. Patients may decrease the dosage or cease taking medication altogether if symptoms improve or may simply forget to take doses.
9. Possible medicolegal considerations. An example is the aminoglycoside antibiotic group, whose use is known to be associated with renal failure in a certain percentage of cases. If a patient develops renal failure while taking one of these antibiotics, the renal failure could be due either to drug toxicity or to the underlying disease. If previous and current antibiotic blood levels are within an established range that is not associated with toxicity, the presumptive cause of renal failure is shifted toward the disease rather than the therapy.
10. Change in dosage or patient status to establish a new baseline for future references.

What factors influence therapeutic drug blood levels?

A great many factors influence TDM blood levels. Discussion of some of the more important follows.

Route of administration. Intravenous (IV) administration places medication into the blood faster than intramuscular injection, which, in turn, is usually faster than oral intake. If IV medication is administered in a few minutes, this may shorten the serum half-life of some medications such as antibiotics compared to methods of administration that take longer. Oral medication may be influenced by malabsorption.

Drug absorption. This may be altered by gastrointestinal (GI) tract motility variations, changes of intestinal acidity, malabsorption disorders, and in some cases interference from food or laxatives.

Drug transport. Many drugs have a substantial fraction that is bound to plasma proteins. Acidic drugs bind predominantly to albumin, and basic drugs bind predominantly to alpha-1 glycoproteins. Protein-bound drug molecules are not metabolically active. Therapeutic drug monitoring using total drug concentration is based on the assumption that the ratio between bound and unbound (“free”) drug remains constant, and therefore alterations in the total drug level mirror alterations in the free drug level. In most cases this is true. However, when 80% or more of a drug is protein bound, there may be circumstances in which alterations in the ratio of bound to free drug may occur. These alterations may consist of either a free drug concentration within toxic range coupled with a total drug concentration within therapeutic range or a free drug concentration within therapeutic range coincident with a total drug concentration within toxic range. This may happen when the quantity of binding protein is reduced (e.g., in hypoalbuminemia) and the dose rate is not changed from that used with normal protein levels. Problems may also arise when the quantity of binding protein is normal but the degree of binding is reduced (in neonatal life and in uremia) or when competition from other drugs displaces some of the bound fraction; interaction between acidic drugs with a high percentage of protein binding (e.g., valproic acid and phenytoin); if metabolism of free drug decreases (severe liver disease); or if excretion of free drug decreases (renal failure). Although an increase in free drug quantity may explain toxic symptoms, it is helpful also to know the total drug concentration to deduce what has happened. In routine TDM, total drug concentration is usually sufficient. If toxicity occurs with total drug levels within the therapeutic range, free drug levels may provide an explanation and a better guideline for therapy. Free drug assays currently are done only by large reference laboratories. The introduction of relatively simple techniques to separate bound from free drug (e.g., membrane filtration) may permit wider availability of free drug assay.

Drug uptake by target tissues. Drug molecules must reach target tissue and penetrate into tissue cells. Conditions such as congestive heart failure can decrease tissue perfusion and thereby delay tissue uptake of the drug.

Extent of drug distribution (volume of distribution). Lipid-soluble drugs penetrate tissues easily and have a much greater diffusion or dispersal throughout the body than non-lipid-soluble drugs. Dispersal away from the blood or target organ decreases blood levels or target tissue levels. The tendency to diffuse throughout the body is measured by dividing the administered drug dose by the plasma concentration of the drug (at equilibrium). This results in the theoretical volume of body fluid within which the drug is diffused to produce the measured serum concentration, which, in turn, indicates the extent of extravascular distribution of the drug.

Drug tissue utilization. Various conditions may alter this parameter, such as disease of the target organ, electrolyte or metabolic derangements, and effect of other medications.

Drug metabolism. Most drugs for which TDM is employed are wholly or partially inactivated (“detoxified”) within the liver. Liver function becomes a critical factor when severe liver damage occurs. Also, some persons metabolize a drug faster than average (“fast metabolizer”), and some metabolize drugs slower (“slow metabolizer”). Certain drugs such as digoxin and lithium carbonate are not metabolized in the liver. The rate of drug metabolism plus the rate of excretion are major determinants of two important TDM parameters. Half-life (biologic half-life) refers to the time required to decrease drug blood concentration by 50%. It is usually measured after absorption has been completed. Steady state refers to drug blood level equilibrium between drug intake and elimination. Before steady state is achieved, drug blood values typically are lower than the level that they eventually attain. As a general rule it takes five half-lives before steady state is reached. Loading doses can decrease this time span considerably. A few investigators use three half-lives as the basis for steady-state measurements.

Drug excretion. Nearly all TDM drugs are excreted predominantly through the kidneys (the major exception is theophylline). Markedly decreased renal function obviously leads to drug retention. The creatinine clearance rate is commonly used to estimate the degree of residual kidney function. When the serum creatinine is more than twice reference upper limits, creatinine clearance is usually less than 25% of normal and measurement is less accurate. In addition, creatinine clearance is somewhat reduced in the elderly, and some maintain that clearance reference ranges should be adjusted for old age.

Dosage. Size and frequency of dose obviously affect drug blood levels.

Age. Infants in general receive the same dose per unit weight as adults; children receive twice the dose, and the elderly receive less. A very troublesome period is the transition between childhood and puberty (approximately ages 10-13 years) since dosage requirements may change considerably and without warning within a few months.

Weight. Dosage based on weight yields desirable drug blood levels more frequently than arbitrary, fixed-dose schedules. One assumes that a larger person has a larger total blood volume and extracellular fluid space within which the drug is distributed and a larger liver to metabolize the drug.

Interference from other medications. Such interference may become manifest at any point in drug intake, metabolism, tissue therapeutic effect, and excretion, as well as lead to possible artifact in technical aspects of drug assay.

Effect of disease on any previously mentioned factors. This most frequently involves considerable loss of renal or hepatic function.

Assay of peak or residual level. In general, peak levels correlate with toxicity, whereas residual (trough) levels are more an indication of proper therapeutic range (i.e., whether the blood level remains within the therapeutic range). Of course, if the residual level is in the toxic range this is an even stronger indication of toxicity. An exception to the general rule is the aminoglycoside antibiotic group, in which the peak level is used to indicate whether therapeutic levels are being reached and the residual level is considered (some disagreement exists on this point) to correlate best with nephrotoxicity. For most drugs, the residual level should be kept within the therapeutic range and the peak level should be kept out of the toxic range. To avoid large fluctuations, some have recommended that the dose interval be one half of the drug half-life; in other words, the drug should be administered at least once during each half-life.

One of the most important laboratory problems of drug level monitoring is the proper time in relationship to dose administration at which to obtain the specimen. There are two guidelines. First, the drug blood level should have reached steady state or equilibrium, which as a rule of thumb takes five drug half-lives. Second, the drug blood level should be at a true peak or residual level. Peak levels are usually reached about 1-2 hours after oral intake, about 1 hour after intramuscular administration, or about 30 minutes after IV medication. Residual levels are usually reached shortly (0-15 minutes) before the next scheduled dose. The greatest problem is being certain when the drug was actually given. I have had best results by first learning when the drug is supposed to be given. If a residual level is needed, the nursing service is then instructed to withhold the dose. The blood specimen is drawn approximately 15 minutes before the scheduled dose time, and the nursing service is then told to administer the dose. If a peak level is needed, the laboratory technologist should make arrangements to have the nursing service record the exact minute that the dose is given and telephone the laboratory. Unless the exact time the specimen was obtained and the exact time the drug dose was given are both known with certainty, drug blood level results cannot be properly interpreted and may be greatly misleading.

Laboratory technical factors. These include the inherent technical variability of any drug assay method (expressed as a coefficient of variation) as well as the other sources of error discussed in Chapter 1. Therapeutic drug monitoring assays in general have shown greater differences between laboratories than found with simple well-established tests such as blood urea nitrogen or serum glucose levels.

Patient compliance. Various studies have shown astonishingly high rates of patient noncompliance with dose instructions, including failure to take any medication at all. Possibly 20%-80% of all patients may be involved. Noncompliance results in subtherapeutic medication blood levels. Some believe that noncompliance is the most frequent cause of problems in patients on long-term therapy.

Therapeutic and toxic ranges

Therapeutic ranges are drug blood levels that have been empirically observed to correlate with desired therapeutic effects in most patients being treated for an uncomplicated disease. The same relationship is true for toxicity and toxic ranges. However, these ranges are not absolute and do not cover the response to a drug in all individual patients or the response when some unexpected factor (e.g., other diseases or other drugs) is superimposed. The primary guide to therapy is a good therapeutic response without evidence of toxicity. Most of the time this will correspond with a drug blood level within the therapeutic range, so the therapeutic range can be used as a general guideline for therapy. In some cases a good response does not correlate with the therapeutic range. In such cases the assay should be repeated on a new specimen to exclude technical error or specimens drawn at the wrong time in relation to dose. If the redrawn result is unchanged, clinical judgment should prevail. Some attempt should be made, however, to see if there is some factor that is superimposed on the disease being treated that could explain the discrepancy. Removal or increase of such a factor could affect the result of therapy at a later date. The same general statements are true for toxicity and toxic ranges. Some patients may develop toxicity at blood levels below the statistically defined toxic range and some may be asymptomatic at blood levels within the toxic range. However, the further the values enter into the toxic range, the more likely it is that toxicity will develop. Thus, patient response and drug level data are both important, and both are often necessary to interpret the total picture.

Some Conditions That Produce Unexpected Therapeutic Drug Monitoring Results
High plasma concentration on normal or low prescribed dose
Patient accidental overdose
Slow metabolizer
Drug interaction that blocks original drug metabolism in liver or injures the liver
Poor liver function (severe damage)
Drug excretion block
Increased binding proteins
Residual level determined on sample drawn after dose was administered instead of before
Laboratory technical factors
Low plasma concentration on normal or high prescribed dose
Poor drug absorption (oral dose)
Interference by another drug
Patient noncompliance
Fast metabolizer
Decreased binding proteins
Peak level determined on sample drawn at incorrect time
Laboratory technical factors
Toxic symptoms with blood levels in therapeutic range
Drug released from proteins (free drug increased)
Drug effect enhanced at tissue level by some other drug or condition
Blood level obtained at incorrect time
Laboratory technical factors
Symptoms may not be due to toxicity of that drug

When to obtain specimens for therapeutic drug monitoring

If a patient develops symptoms that might be caused by a drug, the best time to obtain a specimen for TDM is during the period when the patient has the symptoms (if this is not possible, within a short time afterward). One possible exception, however, is digoxin, whose blood level does not equilibrate with tissue levels until at least 6-8 hours after the dose is given. Therefore, specimens for digoxin TDM should not be drawn less than 6 hours after administration of the previous dose, even if toxic symptoms occur earlier. It should be ascertained how much time elapsed between the onset of toxic symptoms and the time of the last previous medication dose. This information is necessary to determine if there is a relationship of the symptoms to the peak blood level of the drug. If the specimen cannot be drawn during symptoms, the next best alternative is to deliberately obtain a specimen at the peak of the drug blood level. This will indicate if the peak level is within the toxic range. In some instances it may be useful to obtain a blood specimen for TDM at a drug peak level even without toxic symptoms, to be certain that the drug dosage is not too high.

In some cases the question is not drug toxicity but whether dosage is adequate to achieve the desired therapeutic effect. In that case, the best specimen for TDM is one drawn at the residual (valley or trough) drug level, shortly before the next medication dose is given. The major exception to this rule is theophylline, for which a peak level is more helpful than a residual level.

For most drugs, both peak and residual levels should be within the therapeutic range. The peak value should not enter the toxic range and the residual value should not fall to therapeutically inadequate levels.

Information on some of the medications for which TDM is currently being used is given in Table 37-25. The box lists some conditions that produce unexpected TDM results.


Therapeutic drug monitoring can be extremely helpful in establishing drug levels that are both therapeutically adequate and nontoxic. To interpret TDM results, the clinician should know the pharmacodynamics of the medication, ascertain that steady-state levels have been achieved before ordering TDM assays, try to ensure that specimens are drawn at the correct time in relation to dose administration, be aware of effects from other medication, and view TDM results as one component in the overall clinical picture rather than the sole basis for deciding whether drug dosages are correct. Drug monitoring is carried out in two basic situations: (1) in an isolated attempt to find the reason for therapeutic failure (either toxic symptoms or nonresponse to therapy) and (2) to obtain a baseline value after sufficient time has elapsed for stabilization. Baseline values are needed for comparison with future values if trouble develops and to establish the relationship of a patient’s drug blood level to accepted therapeutic range. This information can be invaluable in future emergencies.

Comments on therapeutic drug monitoring assay

To receive adequate service, the physician must provide the laboratory with certain information as well as the patient specimen. This information includes the exact drug or drugs to be assayed, patient age, time elapsed from the last dose until the specimen was obtained, drug dose, and route of administration. All of these factors affect normal values. It is also desirable to state the reason for the assay (i.e., what is the question that the clinician wants answered) and provide a list of medications the patient is receiving.

Some (not all) of the methods used in drug assay include gas-liquid chromatography (technically difficult but especially useful when several drugs are being administered simultaneously, as frequently occurs in epileptics), thin-layer chromatography (TLC; more frequently used for the hypnotic drugs), radioimmunoassay (RIA), fluorescence-polarization immunoassay, and enzyme-multiplied immunoassay (EMIT).

One of the major reasons why TDM has not achieved wider acceptance is that reliable results are frequently not obtainable. Even when they are, the time needed to obtain a report may be several days rather than several hours. It is essential that the physician be certain that the reference laboratory, whether local or not, is providing reliable results. Reliability can be investigated in several ways: by splitting patient samples to be evaluated between the laboratory and a reference laboratory whose work is known to be good (but if isolated values are discrepant, a question may arise as to whose is correct), by splitting samples and sending one portion 1 week and the remainder the next week, or by obtaining standards from commercial companies and submitting these as unknowns. Most good reference laboratories will do a reasonable amount of such testing without charge if requested to do so beforehand.

In some situations, assay results may be misleading without additional information. In certain drugs, such as phenytoin (Dilantin), digitoxin, and quinidine, a high percentage is bound to serum albumin and only the nonbound fraction is metabolically active. This is similar to thyroid hormone protein binding. The (nonbound) fraction may be increased in hypoalbuminemia or in conditions that change protein binding, such as uremia or administration of drugs that block binding or compete for binding sites. Drug level assays measure total drug and do not reflect changes in protein binding. In addition, some drugs, diseases, or metabolic states may potentiate or inhibit the action of certain therapeutic agents without altering blood levels or protein binding. An example is digoxin toxicity induced by hypokalemia.