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Therapeutic Drug Monitoring
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AIDS Action Committee of Massachusetts
www.aac.org
In this issue of Forward Living, we'll focus on "therapeutic drug monitoring" tests used to measure the levels of one or more medications in the body. Therapeutic drug monitoring, or TDM, has been used for years to measure the levels of a variety of medications, including drugs for heart disease, lung disease, cancer, epilepsy, mental illness, and certain infections. TDM may also be used to measure the levels of some HIV medications. We recently spoke with Dr. Cal Cohen, Research Director of the Community Research Initiative of New England (CRI), about TDM and its possible role in HIV treatment.
Question: Before we talk about therapeutic drug monitoring, I'd like to begin by asking a basic question about drug levels: What happens when the level of an HIV drug is too low or too high?
CC: If a drug level is too low, there isn't enough medication to produce the effect you want. In the case of HIV drugs, we want to control HIV infection by substantially reducing the growth of the virus, which leads to a low viral load. On the other hand, if the drug level is too high, the drug can cause severe side effects. So what we want to do is keep the drug level within a particular range high enough to control the virus, but not so high that it causes intolerable or dangerous side effects. Doctors sometimes call this range the "therapeutic-toxic window."
When a new HIV drug is tested, researchers conduct studies to find the "right" dose for the drug balancing drug effectiveness versus the risk of side effects. As a result of this research, a standard dose is determined for the drug. Although the standard dose of a drug works for many people, it doesn't work for everyone.
Question: Why doesn't the standard dose always work?
CC: Even when people receive the same dose of a particular medication, their blood levels can be very different. A number of factors can affect drug levels. One fairly obvious factor is body weight. For example, if a 100-pound person takes the standard dose of a particular drug, they will normally have a higher blood level of that drug than a 300-pound person taking the same dose.
Other important factors include a person's age and metabolism the rate the body breaks down food and chemicals, including drugs. Eating, drinking, and smoking habits can also affect drug levels. In addition, drug levels can be affected by interactions between HIV meds and prescription drugs, over-the-counter meds, herbs, supplements, and street drugs. Finally, pregnancy, menopause, and health conditions, such as kidney or liver problems, can also have an effect on drug levels.
Therapeutic drug monitoring, or TDM, is used to measure the drug levels in a particular person to see if the levels are too low or too high. This information can be used to tailor the dosing of the drug to increase effectiveness or reduce side effects.
Question: I first heard about drug level monitoring several years ago. Why hasn't TDM been widely used in HIV treatment?
CC: There are several reasons. First, many HIV drugs have a fairly broad therapeutic-toxic window. In other words, there is a broad range of drug levels that will control the virus without causing major side effects in most persons. So, for the majority of people, we don't need to know the specific drug level to achieve the effects we want.
Second, it is not currently possible to routinely measure the levels of all HIV drugs. For example, the so-called "nuke" drugs that people take for HIV must be processed inside individual cells into the substances that suppress the virus's growth. So for nukes, the drug level inside the cells is more important than the drug level in the blood. Unfortunately, measuring nuke drug levels inside cells is not yet easily done or readily available with current technology though it is possible to do.
Even when we can measure HIV drug levels, we're not always sure what the "right" blood level is. The "right" level might vary somewhat, depending on the characteristics of the person. The drug level needed to effectively suppress HIV also depends on the characteristics of the virus a person is infected with.
For example, if a person is infected with drug-resistant HIV, they may require a higher drug level to gain viral control. This higher drug level can be reached by prescribing a higher dose of the drug itself or by boosting the level with another drug. The drug level needed to control resistant virus may also vary, depending on the degree of viral resistance.
Another complicating factor is that drug levels vary from hour to hour and day to day. The level of a particular drug can be influenced by many factors, including how recently the person has taken the drug, and whether they have missed any doses in the past few days. As I mentioned earlier, drug levels can also be affected by the consumption of food, medications, or other substances that can increase or decrease drug levels.
Since relatively few labs in the U.S. are currently offering TDM to measure the levels of HIV drugs, doctors may be concerned that a particular lab does not have sufficient experience to measure HIV drug levels correctly. Some doctors may also lack confidence in their ability to properly interpret the results of TDM tests, particularly given all the complicating factors I've just described.
Question: You mentioned that TDM is more practical for some HIV drugs than others. Are there particular drugs for which TDM might be particularly useful?
CC: For now, TDM will probably work best for the protease inhibitors (PIs). For many of the PIs, there is evidence that differences in drug levels can affect the risk and severity of side effects, as well as the drug's effectiveness in suppressing HIV. In addition, a lot of research has already been done on boosting PI levels.
At CRI, we are currently doing a TDM study for people who are on a treatment regimen that includes the PI drugs Kaletra and Invirase. To enter this study, a person must have achieved good viral control (low viral load) with their regimen. However, despite viral control, they may be having side effects, such as high blood fat levels or digestive system problems like nausea and upset stomach, that lead us to consider changing their regimen.
In this study, the Kaletra-Invirase combination is switched to a combination of Reyataz and Invirase, boosted with a small dose of Norvir. We are using TDM to measure the drug levels of Invirase at two different once-a-day doses either 1,200 milligrams (mg) or 1,600 mg. We want to know how the different Invirase doses affect drug levels in the blood, and which Invirase dose works best for each person, both in controlling HIV and minimizing side effects.
CRI is also involved in another study where TDM is being used. This second study is for people who are on regimens containing Kaletra but still have a detectable viral load. In the study, researchers will increase the dose of Kaletra from the usual amount of three capsules twice a day to four capsules twice a day. People in the study will be monitored to see how well this higher dose works. Then, if needed, the dose can be increased further to five capsules twice a day. TDM will be used in this study to measure the blood levels of Kaletra at the higher doses.
FOR MORE INFORMATION
For information about CRI's two TDM trials, please call Karen McLaughlin at 617-778-5454, Ext. 247, or e-mail: kmclaughlin@crine.org.
The HIV Health Library has also collected information about many other HIV studies at research centers, clinics, and hospitals across the state. For more information about these studies, call 617-450-1432 or 866-799-0079, or e-mail: health@aac.org.
AIDS Action Committee: Info_hottopic_01_05
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