Data raises concerns over long-term viability of lower Gleevec doses

By Jerry Call with Norman Scherzer

January, 2005 – One reason that side effects from Gleevec often get better over time is that levels of Gleevec tend to decrease over time in many patients, according to a new report. This may also explain why — although there seems to be no difference in the relationship between dosage levels and initial response to Gleevec — there may be a need for higher doses over time.

Professor Ian Judson

Professor Ian Judson

Dr. Ian Judson, professor of cancer pharmacology at the Royal Marsden Hospital in London, was the lead author in this report by the European Organization for Research and Treatment of Cancer’s Soft Tissue and Bone Sarcoma Group. The study, titled “Imatinib (Gleevec) pharmacokinetics in patients with gastrointestinal stromal tumor …,” looked at Gleevec blood levels from patients in the phase I and phase II trials conducted by the EORTC in patients with GISTs and other sarcomas. Patients with GIST also had repeat sampling after approximately 12 months on Gleevec. While the study is not conclusive, possibly due to a relatively small number of patients, it adds weight to a growing concern that patients treated with lower doses of Gleevec might be at higher risk to develop resistance. The European phase III GIST study recently found a longer time to progression at 800 mg. versus 400 mg. (A smaller U.S. study has not found this). A recent Life Raft Group analysis of patient reported data showed fewer relapses at higher doses — especially when considering the actual dose delivered instead of the “intent to treat” dose.

Pharmacokinetics (PK) is the study of what the body does to a drug. Judson’s study was conducted to examine the variables that affected Gleevec PK, and to determine what changes occurred over time.

Clearance (CL) is one of the primary PK parameters. Clearance describes the efficiency of elimination of a drug from the body. A higher clearance rate means that the drug is being removed from the body faster. Variations in clearance from one person to another or in the same person over time might require an adjustment in dose.

The study looked at several different PK models. In the model that produced the best fit, clearance was correlated with body weight, and granulocyte count. Patients with a lower body weight or with a higher granulocyte count, tended to “clear” Gleevec from the body slower than patients with higher body weight. In their model, a patient with 77 percent of median body weight or with 1.87 times the median granulocyte count, the apparent clearance was 6.53 liters/hour, or about 70 percent of the typical apparent clearance of 9.33 liters/hour.

What this suggests is that heavier patients might need higher doses of Gleevec in order to receive an equivalent dose when compared to a lighter patient. It may also explain why very preliminary research findings by the Life Raft Group suggest that females (lower weights?) in particular seem to respond to higher doses of Gleevec with lower relapse rates.

One of the most interesting findings to come out of this study was that clearance of Gleevec increased by 33 percent in the 12-month period studied. The increase in apparent clearance, if true, should lead to decreasing Gleevec blood levels, and the study found a 42 percent decrease in “area under the curve (AUC),” one measurement of drug blood levels, over the 12- month period.

When Gleevec is administered on an ongoing basis to GIST patients, certain parameters, such as liver function, may change significantly. This leads to a hypothesis that clearance might increase in GISTs requiring Gleevec, which usually contain liver metastasis, because liver functions may improve as a result of tumor shrinkage. A European study of this question has just begun, according to Dr. Jaap Verweij of Erasmus University Medical Center, Rotterdam.

Dr. Jaap Verweij

Dr. Jaap Verweij

Volume of distribution (V) is the second major PK parameter. It is a little more complex than clearance. For starters, it is not a real “volume.” It is the concentration of a drug in the plasma (the fluid noncellular, portion of blood) in relation to the total amount of the drug in the body. Volume of distribution is an imaginary volume; the major determinant is the relative strength of binding of the drug to tissue components as compared to plasma proteins. Volume of distribution will be higher where most of the drug is distributed to tissues and less of the drug to plasma. Conversely, volume of distribution will be lower in drugs where most of the drug is held in plasma and less drug is distributed to tissues.

In this study, hemoglobin levels affected the volume of distribution of Gleevec. Low hemoglobin levels correlated with low volume of distribution. For a patient with 84 percent of the typical hemoglobin level, the volume of distribution was about 70 percent of the typical volume of distribution. In simpler terms, this suggests that higher hemoglobin levels helps the Gleevec leave the blood and get into tissues, including tumors.

This finding is supported by a EORTC presentation given at the November meeting of the Connective Tissue Oncology Society (CTOS). This presentation, given by Martine Van Glabbeke, reported low hemoglobin levels as a significant prognostic factor in initial resistance to Gleevec (progression within three months).

While the study investigators noted that alpha-1-acid glycoprotein levels were considered to be potentially important, they were not measured for this study.

The study raises practical questions:
— Would phasing-in higher doses of Gleevec improve compliance and response rates? There is a study is the planning stage that is designed to answer the question of compliance, according to Verweji, but the study can only be done if financial support can be obtained. “The protocol as it currently is foresees a start at 400 mg. and then a stepwise increase to 800 mg. over a period of two months [time still under discussion],” Verweji said. “The protocol objectives are to try and increase the percentage of patients that tolerate 800 mg. in the long term.”
— Is there the need for an expanded role for clinical interventions to raise hemoglobin levels, such as epoetin alfa (Procrit) or transfusions? “There is still a lot of uncertainty” said Verweij. “If is far too early to draw any scientific conclusion at this point. One could not yet justify this approach.”
— Can certain variables, such as body weight, granulocyte count, hemoglobin levels, drug-related side effects, and response be used to adjust Gleevec dosage levels? Dr. Ian Judson, Royal Marsden Hospital, London, responded to this question for us. “What we cannot do is use these limited PK data to suggest modifications in imatinib (Gleevec) dose according to haemoglobin, WBC, or liver function, etc. The trend to increased clearance over time may contribute to improved drug tolerance but acquired resistance is due to new mutations and a substantial dose increase may then be effective in a percentage of patients, as reported.”

The study’s conclusion noted “Given the large interpatient variability in clearance and AUC, it is currently not possible to determine whether or not PK factors might play a role in the development of resistance to imatinib. Mutations affecting the KIT binding site and activation of alternative proliferative pathways offer more likely explanations. However, stabilization of progressive disease following an increase in imatinib dosage has been described …. Increasingly, knowledge of mutation type can be used to predict the response of GIST to imatinib. Further work is required to determine whether or not a late increase in imatinib clearance truly does occur in GIST patients and the extent to which this contributes to alterations in response and disease control.”

This study gives additional insight to some practical concerns in the treatment of GIST patients. While the results of this study are not definitive, GIST patients and their doctors must often make many decisions based on incomplete or immature data. This study gives GIST patients a little more information with which they can make these difficult decisions.

Jerry Call is science coordinator of the Life Raft Group. Norman Scherzer is the group’s executive director.