5 replies to this topic

[Trey]

The abstract below makes several interesting points about a study of Gleevec plasma concentration levels and dosage.  First, although Gleevec plasma concentrations increased when dosage went from 400mg to 600mg, the concentrations did not increase as much as one might expect (only increased from 1325.61 ng/mL to 1550.90  ng/mL).  A second and maybe more interesting point is that female patients had significantly higher Gleevec concentration levels than the male  patients for the same dosage.  I think this is our experience on this Board where we see many more women have low blood counts than men, which might show that women have more effects from a particular Gleevec dosage than men.  If this is true, then one might wonder if 300mg dosage Gleevec for women might be close to equivalent to 400mg dosage Gleevec in men (or 400mg in women acts like 500+mg in men, or some other relationship).  That is just my unscientific extrapolation from this study and other info I have seen, plus our own experiences here.  Also, Chinese patients have a higher plasma level concentration on average than caucasian patients for the same dosage, which brings up the issue of body size vs. dosage.  We have been told that size does not matter (? !!!) when it comes to dosage (Pat -- you jumped to a conclusion there, didn't you), but this study suggests otherwise.  And a final point made was that molecular responses did not correlate to increased dosage, but more to "time elapsed before Imatinib therapy".  All very interesting points.  As with any study, there are unknown variables, and the patient population is only 46 patients.  You decide:

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients.

Acta Pharmacol Sin. 2010 Jul 19;

Authors:  Li QB, Chen C, Chen ZC, Wang HX, Wu YL, You Y, Zou P

AbstractAim:To investigate the pharmacokinetics of imatinib in  Chinese chronic myelogenous leukemia (CML) patients.Methods:Fourty-six  naive Chinese CML patients treated with imatinib (400 and 600 mg daily,  n=36 and 10, respectively) were recruited. The correlations of imatinib  (400 mg) trough plasma concentrations (C(mins)) with the patients'  characteristics and responses were analyzed.Results:The overall mean  (+/-SD, CV%) steady-state C(mins) for imatinib at 400 mg (n=36) and 600  mg (n=10) daily was 1325.61 ng/mL (+/-583.53 ng/mL; 44%) and 1550.90  ng/mL (+/-462.63 ng/mL; 30%), respectively, and no statistically  significant differences were found between them (P=0.267). At 400 mg  daily, female patients had significantly higher C(mins) than the male  patients (P=0.048), and molecular responses were not correlated with  imatinib C(mins), but they were correlated with time elapsed before  imatinib therapy. Conclusion:The results suggest that Chinese CML  patients have higher imatinib C(mins) than their Caucasian counterparts  and that the optimal initial imatinib dose for them requires further  investigation.

PMID: 20644548 [PubMed - as supplied by publisher]

[threedprof]

i wondered what the concentrations meant.  I had mine done about 6 months ago and it came back at 600 ng/mL on the 400mg dosage.  my onc spoke with Dr. Druker about this and he said because 400mg has been working so well for so long he didn't find it necessary to change my dosage, upward.  SO my question is: what does this number really mean?  I know it's the amount circulating around your blood BUT does this mean that there's still Leukemic cells floating around taking up the other 400 ng/mL?  Since the base they like to see is 1000 ng/mL.

Just curious,

Joel

[Trey]

The test measures the amount of Gleevec floating around in the plasma (fluid part of the blood), not what is inside the blood cells.  The drug in the plasma is considered available for uptake into the cells, which is where it does its work.  Gleevec in the plasma does not inhibit BCR-ABL; it must be taken into the WBC to inhibit BCR-ABL.  Your plasma level (I assume measured at 24 hours after taking the Gleevec) is quite low compared to the 24 hour 1000ng/ml level suggested as the desired therapeutic level based on studies.  This level assumes that after 24 hours much of the drug has already been taken up into the WBCs.  But your results show how much variation can occur among patients.  Your cells must be very efficient at taking Gleevec into the cells (via a cell "pump" called hOct1).  Possibly your plasma level is low because so much is taken into your WBCs, but I do not know.  So while many people may need 1000ng/ml, you do better than most on much less drug, since another posting said you have been PCRU for several years.  By the way all WBCs take in the Gleevec, not just the leukemic ones.  To the cells, they "drink" whatever is in the plasma that is small enough to enter.  Since Gleevec is a small molecule drug, if the plasma has Gleevec floating around, it will be pumped in with everything else.

[hannibellemo]

I admit I may have wondered where the heck you were heading, Trey, but this is a very interesting topic.

Consider research for treatment for heart disease where the vast majority of participants studied were men (were they all men?) and how the standard of care and treatment that was determined from that research doesn't necessarily carry over for women. It stands to reason that if women's physiology is so different in that respect why wouldn't that be true with other disease processes and treatment standards?

Also, at 5' 11", I am way above average in size for women and men, for that matter, but I experience the same low counts that so many other women on these boards do.

We know the CML phase breakdowns for the participants in the IRIS study but what percentage of those 500+ participants were women? I ask this because I've read that the average age at Dx for CML is 72 and it affects men more often than women.

Pat

[Matt]

I have a few questions, and this seems like a pretty good place to ask them. I have been taking Gleevec (400mg/day) since I was diagnosed in 1/09. At first, my response to the Gleevec was very good. My blood counts have all gone back to normal ranges, all of my symptoms are gone, and I really haven't had any side effects to the medication. However, my past three PCR tests (taken over the past year) have shown a "plateau" in my level of leukemic cells. Although my blood work all looks good, there is still a very measurable amount of leukemic cells in my blood (nowhere near PCRU). After each of the first two PCR tests, I brought up to my doctor the option of increasing my dosage, but she seemed to be comfortable with my levels. She felt that, as long as my levels did not begin to trend back up again, my response to the Gleevec, although not ideal, was "acceptable". After each PCR, I also suggested that we perform a Gleevec Blood Level Test (which my doctor seemed to have never heard of). My rationale was that my numbers are remaining at such a close level that maybe the Gleevec is fully metabolizing before it reaches all of the leukemic cells. That possibility seems even more likely to me when I consider that I am a big guy (6'5", 240 lbs), young (28), and very active. Since the result of my most recent PCR test supports this "plateau", my doctor is now thinking of increasing my dosage to 600mg/day. She is also (finally) researching the Gleevec Blood Level Test to see if that is something we should do. Now for my questions:

Could my rationale for this "plateau" have any basis, and if so, would the Gleevec Blood Level Test give me an indication of this? Should I take the test while I am still taking 400mg/day in order to get a baseline to measure the effect of the increase in dosage? Is the test still FREE? (I tried to find info about it this weekend, and the website seems to be "temporarily unavailable". I also tried calling Novartis, and they seemed to side-step the question.) Should I have my doctor test for anything else (such as mutations, etc.) before we make a change? If you have any other advice or suggestions, I would be happy to hear them! This will be my first adjustment in treatment since I was diagnosed, and as you might imagine, I am certainly anxious about it. I expect to have a long life ahead of me and just want to make the best decisions that I can for myself and my family. Thanks!

[Trey]

Your reasoning is good, in my opinion.  Hopefully your plateau level is at least a 3 log reduction.  You are seeing that Gleevec will probably not take your levels lower, at least not very quickly.  It is better to see steadily declining numbers (on average) over time.  So either an increase in Gleevec dosage or a switch in drugs would be a reasonable approach, and if it were me, I would do one of those.  And a Gleevec Plasma Level Test before an increase in Gleevec dosage would provide some useful info, although just increasing the dosage would also show you if the increased dosage works for you.

Novartis' U.S. website (where the free plasma level test was offered) has been shut down temporarily because the FDA was not happy with how Novartis was advertising their drugs:

http://www.foxbusiness.com/story/markets/industries/industrials/update-fda-warns-novartis-gleevec-related-websites/