All About Gleevec (Glivec)

This report is based on analysis of the pharmacokinetic data from the original phase II Gleevec trial for GIST (B2222), which started in July of 2000. Plasma levels (plasma is one component of blood) taken after 29 days of Gleevec, were available for 73 of the 147 patients enrolled in the trial. These plasma levels were grouped into quartiles according to imatinib trough plasma concentrations (the level of drug in the blood at its lowest point during the day, just before taking the daily Gleevec capsule).The plasma levels and response rates of these groups are listed in the table below.

Plasma levels and response rates

The authors concluded that, “Exposure to adequate drug levels of imatinib appears to correlate with clinical benefit; patients with the lowest imatinib levels show lowest objective response and shortest time to progression. These results suggest that monitoring pharmacokinetic/ pharmacodynamic relationships may provide novel predictive markers and that exposure to adequate IM trough plasma concentrations (>1,110 ng/mL) is important for optimal clinical response.”

A video report is available on the medpageTODAY website. In the interview, Dr. Demetri explained that “when you give Gleevec or any other kinase inhibitor to a group of patients, they will handle it very differently, some people will have high levels and some people will have low levels… The important part about that is whether we for years might be underdosing people, and whether we perhaps should develop a blood test to check the levels of this drug in people’s blood and have more certainty that there’s actually therapeutic levels in the blood.” Demetri went on to explain that “it’s possible that we could have done this analysis and found nothing at all, but in fact, we saw something that is a bit worrisome for the patients with the lowest levels of the drug.” The next step according to Demetri will be to “… talk with our colleagues, decide exactly how much this is worth pursuing, (and) decide how to mount a large trial.”

Plasma Level Trial Terminated

In January, 2010, a phase III trial testing the effect of plasma testing started in the U.S. In March 2011, this trial was terminated due to a lack of recruitment. With no other ongoing trials testing plasma levels in GIST, it does not look like there will be any definitive data to establish whether or not maintaining plasma levels above a certain level will have benefit in GIST.

Blood Level Testing

In March, 2010, Novartis Pharmaceuticals received a warning letter from the U.S. Food and Drug Administration (FDA), expressing concern over web sites sponsored by Novartis. As a result Novartis immediately suspended these web sites and support for plasma testing in the United States. Despite the termination of Novartis support, Dr. Linyee Shum, the Executive Director and Chief Scientific Officer of TDM Pharmaceutical Research has graciously offered to continue to provide blood level testing to the GIST patient population. The target date for resumption of testing is May 16, 2011. Read the full story in the April 2011 LRG Newsletter: Breaking news update: TDM renews plasma testing

Imatinib plasma level testing may be available in other countries for residents of those countries. Some of the sites that we are aware of are listed below.

Related Links

Plasma level testing: what we know, what we don't & what we hope to learn

Is there a role for drug level testing?

Routine mutational and plasma level testing: the time has come

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References

1.Imatinib Plasma Levels Are Correlated With Clinical Benefit in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumors (full text)

George D. Demetri, Yanfeng Wang, Elisabeth Wehrle, Amy Racine, Zariana Nikolova, Charles D. Blanke, Heikki Joensuu and Margaret von Mehren

2. Drug plasma monitoring in CML and GIST: A case-based discussion.
Egorin MJ, Mauro MJ, Trent JC.

3.Trough imatinib plasma levels in patients treated for advanced gastrointestinal stromal tumors evidence of large interpatient variations under treatment with standard doses.

B. N. Bui, A. Italiano, A. Miranova, S. Bouchet, M. Molimard

4. Personalized cancer therapy for gastrointestinal stromal tumor: synergizing tumor genotyping with imatinib plasma levels.

Marrari A, Trent JC, George S.

5. Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Margaret von Mehren, Nicolas Widmer

6. Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST)
G. D. Demetri, Y. Wang, E. Wehrle, C. Blanke, H. Joensuu, M. von Mehren