In this article we discuss drug level testing. Clinical trials have given us a lot of information about dosing Gleevec. Unfortunately, however, doctors and researchers do not always reach the same conclusions about what the data is telling them. Measuring Gleevec drug levels in patients may provide a measure of reassurance to patients and doctors that they are on the right course with regards to dosing.

In early CML clinical trials, a large variation in drug levels was noted between patients taking the same dose of Gleevec. Despite this large variation, how a patient responded was found to be more dependent on the dose they were taking compared to their blood levels (Cmax or Cmin). These early results may have led many experts in the field to conclude that monitoring blood levels in the clinic was not necessary. Given some of the new and perhaps conflicting research, it may be time to reexamine the need for blood level testing.

Recent data from the GIST reGISTry indicates that 72 percent of patients are prescribed Gleevec at 400 mg/day. A dose of 300 mg/day is generally considered to be at the lower end of the therapeutic range for Gleevec. Research into the pharmacokinetics of Gleevec in GIST patients has suggested that Gleevec blood (or serum) levels drop over time (EORTC study; Judson et al.). In fact, Gleevec levels may drop 30 to 40 percent over the course of the first year on Gleevec. What happens to those patients that start at 400 mg/day and have a 30 to 40 percent reduction in Gleevec levels? In theory, they may receive a dose of Gleevec equivalent to taking 240 mg to 280 mg/day.

What causes the reduction in Gleevec blood levels over time? At least three different theories have been put forth that might explain this phenomenon:

1. Gleevec clearance increases over time-possibly related to improved liver function (Judson et al.); in other words, the body becomes more efficient at removing Gleevec.

2. Multi-drug resistance proteins are induced over time decreasing the transport of Gleevec across the intestinal membrane (Burger et al.).

3. Patient adherence to taking the drug falls off over time (Tsang et al. and Feng et al.).

The first two items are out of the patient’s control, but the third is not. The practical problem that patients face is that one, two or all three of these theories could be correct with different implications. If patient adherence was the primary cause of dropping Gleevec levels, then only less adherent patients would have to be concerned; but if Gleevec clearance increased or multidrug transport was the problem then all patients stand to be affected.

Monitoring Gleevec blood levels over time would remove the question from the realm of the theoretical and place it into the realm of the practical. From the patient’s point of view it would not matter which theory was correct; if drug levels were monitored and shown to drop, the Gleevec dose could be raised to compensate.

Increased patient education about the need for patient adherence to taking their medication is needed. This goes hand-inhand with better side effects management. Better adherence does not totally remove the need for drug testing because, with the present data, patients cannot exclude the other possibilities for reduced drug levels.

Another potential problem that patients face is drug interactions. Gleevec affects and is affected by drugs that inhibit or induce certain liver enzymes. Gleevec is most affected by the liver enzyme CYP3A4, but is also affected by CYP2D6. Drugs that induce these enzymes cause Gleevec levels to drop; drugs that inhibit these enzymes cause Gleevec levels to rise. Monitoring Gleevec blood levels provides a backup to the doctors and pharmacists ability to anticipate and correct these drug interactions.

While testing Gleevec blood levels is not commercially available, it is clinically available. Dr. Merrill Egorin of the University of Pittsburgh is able to provide doctors with Gleevec blood level testing. At the present time there is no charge for this testing. Doctors interested in having their patients’ Gleevec levels tested should contact Dr. Egorin at the University of Pittsburgh Cancer Institute.

The Life Raft Group staff has begun talks with Dr. Egorin and other GIST experts about the expanded use of Gleevec blood level testing. We believe this testing might be particularly useful for monitoring blood levels over time and for other situations such as monitoring for potential drug interactions. The results must be interpreted with caution as Gleevec blood levels are not an absolute indicator, especially when looking at a single point in time. In particular, variations in protein binding between patients can produce misleading results.