Therapeutic drug monitoring (TDM), an important element in patient care, is the measurement of medication and metabolic concentrations in blood that will directly influence drug dosing. Its main focus is on drugs that can easily be under- or overdosed. It is a branch of clinical chemistry that is also handled by clinical pharmacy, clinical pharmacology, and specific medical specialists with or without the use of a laboratory at all, according to Philip D. Walson, professor of Pediatrics & Pharmacology, University of Cincinnati, and director, Clinical Pharmacology Division and Clinical Trials Office, Cincinnati Children’s Hospital Medical Center.

Occasionally, medications are used without monitoring of blood levels, as their dosage can generally be varied according to the clinical response a patient has to that substance, and physicians can use other tests such as blood pressure or temperature to tell if the dosage is correct. Walson says there are many drugs for which no objective or clinically meaningful objective signs or symptoms exist, and many others for which over- and underdosing produce similar symptoms (for example, digoxin produces arrhythmias if too much or too little is given, as do anticonvulsants and antiarrhythmics). In addition, he says, even for drugs for which effects can be measured, it can occasionally be useful to quantify concentrations such as in overdose or to document that noncompliance rather than resistance to a drug or its unusually rapid clearance is responsible for lack of effect. “TDM is routinely used for only a few drugs but can be useful in specific instances for almost all drugs,” he says.

But in a small group of drugs this is impossible, as insufficient levels will lead to undertreatment or resistance, and excessive levels to toxicity and/or tissue damage, according to pharmaceutical manfacturers. Walson says the group, however, is not so small. He says use is limited by the availability of assays and TDM expertise, and is not a characteristic of many drugs at all. Since compliance is routinely common and results are accurately provided by most clinicians, some would argue that TDM is required for all drugs, he says.
TDM can also detect poisoning with drugs, should the suspicion arise. The importance of TDM is self-evident, both in determining the most effective doses for treating certain diseases and avoiding drug toxicity. Drugs commonly monitored include those for heart disease, bacterial infections, epilepsy, asthma, chronic obstructive pulmonary disease (COPD), certain cancers, arthritis, and psychiatric disorders, and those designed to prevent rejection of transplanted organs.

The drugs that are monitored have some special features; most of them work best over a narrow therapeutic range. Below this range, the drug is not effective and the patient begins having symptoms again; above this range, the drug has negative, adverse, or toxic side effects. Since many people take more than one medication, there may be interactions between the drugs that affect the way the body absorbs or metabolizes one of them. Also, some patients do not take medications as prescribed or instructed. Monitoring helps identify these cases of noncompliance.

According to Walson, the “therapeutic range” is also misunderstood; it is variable, not absolute, and the pharmacokinetics of a drug must be understood to know whether the patient is at steady state. This will help determine whether a concentration within or outside the “therapeutic range” is going to be in, above, or below that range during part or even most of a dosing interval. Misunderstanding of the therapeutic range is responsible for many therapeutic misadventures. Clinicians and, unfortunately, too many laboratorians do not understand either the individual variations in this range or the dynamic nature of concentrations over time or during the approach to steady state. In fact, “steady state” (which is anything but “steady”) is also often misunderstood, Walson says.

Some History
TDM became feasible for most clinical laboratories in the 1970s with the development of semiautomated immunoassays for common therapeutic drugs. Previously, more sophisticated methodologies, such as high-performance liquid chromatography, were necessary, and TDM was not a routine laboratory function, according to Dave Armbruster, PhD, scientific affairs manager, Global Scientific Affairs, Abbott Diagnostics. When new and simpler analytical methodologies made TDM more accessible, it quickly became a routine subspecialty in laboratories and a wide variety of drugs were tested, including cardiac antiarrythmics, antiepileptics, antiasthmatics, antibiotics, and immunosuppressants.

The Importance of TDM
Clinical labs play a vital role in TDM, and they continue to expand this critical support. TDM is just one of three key areas of laboratory drug testing, says Kelli Ryzewski, director of drug-testing marketing for Dade Behring. The other two areas are testing for drugs of abuse and immunosuppressant drug monitoring, an area that continues to grow as new immunosuppressant drugs enter the market. One example of effective TDM is monitoring for the antiepileptics. “The antiepileptic drugs were introduced in the 1960s, but establishing the right dosage for the best therapeutic result was difficult for physicians. While it was possible to measure blood levels for these drugs, the methods were difficult and time-consuming. Dade Behring looked at ways to meet the need for fast, easy therapeutic drug testing. We developed the Syva EMIT technology to make TDM testing practical and effective in any clinical lab. Dade Behring now offers 24 different TDM assays, with 10 more in our pipeline, and Syva EMIT still stands as the gold standard for TDM testing,” she says.

Walson notes that people are still dying from inadequate use of antiepileptic TDM. “But fortunately, we now have drugs for which the therapeutic margin is much larger than before. However, even the newest drugs can be used more effectively with appropriate TDM. This is also a good example of drugs introduced as ‘not needing TDM’ as a marketing strategy where we now know that TDM can be very useful in specific patients,” he says.

Ryzewski says that TDM has become an integral part of managing patient care. Laboratories and clinicians have become comfortable with the process, and immunosuppressant drug monitoring has moved into the forefront of TDM. Patients need to stay on immunosuppressants, because acute and chronic rejection are real concerns for transplant patients. Too large a dosage of a drug can cause toxicity and lead to organ damage, while too little a dosage can lead to organ rejection. Symptoms and reactions must be continually checked to prevent rejection. These tests are done almost exclusively with blood samples, although Ryzewski says oral fluids are used in rare instances. Rapid turnaround time for results is usually necessary.

Walson says that cardiac arrhythmias, seizures, and serious infections are all as likely to kill a patient as improper immunosuppressant. Immunosuppression is merely the newest, and perhaps most dramatic, use of TDM, but it is not the exclusive use that saves lives, he says.

Judith A. Britz, PhD, CEO of Cylex Inc, says TDM tests are now easier for manufacturers to develop because the US Food and Drug Administration (FDA) loosened regulatory restrictions on them by reclassifying TDM assays from Class III to Class II devices. As a Class II device, physicians now must use TDM results in combination with other tests and clinical information instead of relying solely on the drug level to make changes in therapy. They cannot rely on TDM tests exclusively, because they also have to determine how a patient may individually respond to a given drug—whether this is genetically predetermined or reflects an individual’s unique metabolic profile. Traditionally, pharmacokinetic studies measured drug levels over time. It is now just as critical to assess the impact of the drug or combination of drugs on the target organ, a pharmacodynamic measurement, Britz says.

With immunosuppressants, such as calcineurin inhibitors, antiproliferatives, and steroids, clinicians need to know if the drug combination is effective, so the impact on the immune response system must be measured. However, transplant recipients seldom receive a single drug, and there is no algorithm using TDM levels to determine the aggregate effect on the immune system. Cylex’s ImmuKnow™ product provides pharmacodynamic measurement that allows the assessment of the patient’s net state of immunosuppression on CD4 cell function.

Walson says there are good examples of why both TDM and other tests are useful. A patient with a lack of immune suppression would have to have concentrations measured to be sure that noncompliance (the single most common cause of kidney-transplant rejection in adolescents, for example) is not the reason, rather than any resistance to drug effects. The FDA has not demanded that TDM be replaced, merely that it be supplemented with tests such as these biomarkers.

“TDM is OK when a patient is taking only one drug,” Britz says. “But as soon as a patient takes a second drug, the impact of that needs to be known.” She says TDM is valuable in detecting noncompliance and toxicity, but the FDA requires it to be used in concert with other things. Other clinical assays are needed to determine each patient’s context, and biomarkers of the impact of the drug.

TDM assays are very specific tests, she continues, because they determine the analytical levels of a specific drug. ImmuKnow, which received clearance from the FDA in 2002, measures the cumulative impact of drugs on the immune system. Britz says it’s not a replacement for TDM but a “necessary adjunct test for anyone who uses drugs that affect the immune system.” But Walson says that fortunately or not, immunoassays are not so specific.

 The ImmuKnow test uses whole blood since many of the immunosuppressants are intercalated into red-blood-cell membranes and should remain present during the overnight stimulation with PHA. After stimulating the cells overnight, the CD4 positive cells are selected out of the blood, and if they’ve been activated, they will produce intracellular ATP, which can be measured with luciferin/luciferase in a luminometer. Britz says ImmuKnow is unique—one of the first and only such tests that has received FDA clearance for the detection of cell-mediated immunity in an immunosuppressed population.

“Physicians recognize that therapeutic drug levels are influenced by many factors, such as genetics and individual metabolisms, and that while TDM assays are and will remain important, they are incomplete in providing doctors with all they need to assess the impact on drug therapy,” Britz says.

Alexander A. Vinks, PharmD, PhD, professor of pediatrics and pharmacology, University of Cincinnati, and director of the Pediatric Pharmacology Research Unit (PPRU) and Laboratory of Applied Pharmacokinetics and Therapeutic Drug Management at Children’s Hospital Medical Center, Cincinnati, agrees that TDM can play a decisive role in disease management, “but the way we deliver this type of service misses an opportunity to impact on disease management.”

Like others, Vinks notes that TDM is mostly important in organ transplants and in monitoring anti-epileptic drugs, antibiotics, and older drugs like digoxin. Ryzewski adds that monitoring cardiac drugs (such as digoxin) that have a very small therapeutic range is important. Labs traditionally generate numbers and provide clinicians with a range within which the numbers should fall. But with TDM, the concentration of a drug in a patient can differ from the time of ingestion to the time of excretion. “It fluctuates. That’s where the complications set in, so many labs test at troughs—just prior to the next dose—as well as at peak levels. But trough levels are often not good measures to detect the effects of the drugs, because concentrations would be higher at ingestion. “This method is OK, but not optimal. It’s like trying to buy a suit in a size range, rather than the exact size,” Vinks says.

This is the point Walson made earlier about temporal changes in concentrations (Pharmacokinetics—PK), and pharmacogenetics, the ability to determine whether a patient is genetically likely to have a rapid or slow clearance of a given drug or group of drugs, is also significant. This can even help predict who is most likely to have drug-drug or drug-diet interactions, and can be extremely useful in deciding whether compliance, drug interactions, or rapid clearance are responsible for unexpected concentrations or effects.

The Changing Role of the Lab
Vinks says this is what the role of the lab could be: offering a more multidisciplinary type of service and playing a more important role in interpretation—in other words, a more proactive role. This could mean testing at times other than in the trough. In some fields, such as transplantation and oncology, where the impact depends on the difference in patients, it’s important to individualize testing. In HIV treatment, for instance, underdosage of therapeutic drugs leads to ineffectiveness, while overdose leads to toxicity, and there are similar concerns when treating epilepsy and psychiatric disorders. It’s necessary to know how quickly therapeutic drugs are being metabolized. Vinks chaired a symposium on this trend at the American Society for Clinical Pharmacology and Therapeutics (ASCPT)’s 2006 Annual Meeting in March.

 Alexander A. Vinks, PharmD, PhD

Vinks and Walson say labs have an important role to play in interfacing with patients and in interpreting results for physicians. One problem is reimbursement. Another is that the industry hasn’t been able to come up with hard data to show that an investment in pharmacokinetics is cost-efficient. Patients and physicians alike should demand better and more pharmacokinetic (and pharmacodynamic) education, Vinks says. He thinks labs need to go beyond the TDM functions they currently perform. They must know pharmacokinetics as well as pharmacodynamics.

“Someone has to collect pharmacokinetic information, and I feel it’s the lab’s responsibility,” Walson says. “The vast majority turn their results over to physicians without interpretation. That’s not acceptable.”

But not all lab personnel are trained to interpret results as they are in Europe, Walson says. In the future, merely knowing drug levels will be useless unless results are correctly interpreted. Intelligent systems are needed to help interpret drugs more easily. This is especially important in transplants, where monitoring immunosuppressant drug effectiveness is vital to guard against rejection of transplanted organs. These intelligent systems need to be integrated with hospital pharmacy and nursing drug-administration systems, Walson says.

Some drug companies maintain that monitoring is not necessary; but it is necessary for patient safety and disease management. One reason labs have been reluctant to embrace TDM is that they consider reimbursement inadequate.

Ryzewski says that immunosuppressant testing is migrating into central clinical labs more as new technology is developed and the tests become easier to perform. She adds that it’s important to have assays to monitor any new drug with a critical therapeutic range. The best in quality patient care happens when pharmaceutical and clinical diagnostic companies work closely together in developing the drugs and the assays necessary to monitor those drugs. “I think labs play a critical role in getting clinicians the information they need to optimize drug treatment,” she says.

The Future of TDM
Armbruster sees a continuing role for TDM, and says the current rationale for performing TDM will not change in the foreseeable future. Today, Ryzewski says, while TDM testing averages less than 10% of a clinical laboratory’s test volume, it plays a very important role. She agrees that TDM will always be important to ensure that patients are not approaching toxicity, that they are compliant with their drug regimen, and that they are taking an effective dose.

Armbruster suggests that the acronym TDM remains unchanged but instead of “therapeutic drug monitoring,” it should be “therapeutic drug management.” “Monitoring suggests that TDM focuses on the analytical process in the laboratory and less on the clinical value of the testing. Management suggests that TDM is a key component of patient care and serves to tie laboratory testing more closely to medical treatment,” he says.

TDM is no longer just an umbrella term for a collection of individual drug tests that may be ordered,    Armbruster says. Instead, it is a significant service component of the clinical laboratory. Laboratories are no longer content to provide only a drug concentration/result to health care providers, but strive to present TDM results as valuable medical information that can directly improve patient outcomes and ensure patient safety.

Vinks foresees a time when drug exposure and response could be accurately predicted even before the first dose is given. Instead of administering a standard dose, available demographic and clinical data would be entered into a personal digital device; the model and software would then generate an individualized dosing regimen. That would enable physicians to predict whether the drug and dosing regimen selected would give the best possible response with the least likelihood of side effects.

And even if the number of drugs analyzed by TDM remains stable, total TDM test volume is expected to increase in the future simply because the population is aging and more patients are beginning long-term drug therapy, Armbruster says. “There’s little doubt that TDM will remain a critical subspecialty in the clinical laboratory,” he says.

Gary Tufel is a contributing writer for Clinical Lab Products.