Blood plasma levels of imatinib (Gleevec) may predict clinical response

At the January 2008 ASCO GI Cancers Symposium Dr. Demetri presented regarding how the measured level of imatinib (Gleevec) in patients’ blood plasma correlated with their treatment outcome. The paper was “Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST)” by G. D. Demetri, Y. Wang, E. Wehrle, C. Blanke, H. Joensuu, M. von Mehren.

The subjects were a portion (N=73) of the patients in the B2222 trial (Phase II imatinib trial). The blood plasma levels of Gleevec were measured on the first day they took it and on Day 29. The Day 29 measurements were used in this evaluation because they are the “steady-state” levels achieved after the body has been on the drug for a while. Investigations of imatinib pharmacokinetics in normal test subjects have shown that people differ a lot in how fast their bodies process and excrete Gleevec. This study looked at the minimum blood plasma concentration (“trough” levels) occurring just prior to taking the next dose. This was abbreviated as Cmin in the study. The trough levels correlated with clinical benefit better than either maximum levels or “area under the curve.”

Age, gender, and body weight did not predict trough levels. Trough levels were not proportional to dose (400 versus 600 mg/day); that is to say that mean plasma levels for 600 mg were NOT 1.5 times that for 400 mg. There was wide overlap in plasma levels for dose groups due to individual differences. There was a large amount of variability among patients.

Because patients could not be grouped by dose taken, they were divided into 3 groups according to measured plasma trough level of imatinib:

• those in the lowest quartile for Cmin (the 25% of patients with the lowest blood levels of drug, N=18),
• those in the 2nd and 3rd quartiles (quartiles surrounding the median, N=36),
  and
• those with the highest blood plasma levels of Gleevec (4th quartile, N=19).

The major findings were:

• Large inter-patient variability in imatinib pharmacokinetics result in differing exposures to the drug for people taking the same dose per day
• Patients in the lowest quartile of blood plasma levels of imatinib had lower rates of objective response and clinical benefit (stability or objective response) and a shorter time to progression (but not significantly shorter overall survival) than the 2-4 quartile groups with higher blood plasma levels of Gleevec (which did not differ from each other). This suggests that a minimum effective level of drug must be attained for disease control: approximately greater than 1100 ng/mL.
• Among exon-11-mutation patients (N=39, the largest group) the differences were statistically significant: patients with plasma levels of imatinib in quartiles 2-4 showed higher percentages of clinical benefit and a longer time to progression.
• There were not enough exon-9-mutation patients or other mutation-status patients to detect a significant difference in these groups.
• More study of imatinib (Gleevec) pharmacokinetics is needed to confirm and expand these hypotheses. Individual people vary in factors that influence their blood plasma levels of drug, including plasma albumin and white blood cell counts.