Ibrutinib dosing rationale for CLL at 420mg per day

[ThreeWs]

The link provided below is a full research paper from the respected "New England Journal of Medicine" July 2013, lead author J.C. Byrd et al. but the "et al." contains a host of the best CLL experts one could ask for to include Richard R. Furman who donates valuable guidance on CLL/SLL forum and Jeff P. Sharman familiar to many because of his Blog.

If I were in need of negotiating with doctors and or insurance companies to get Ibrutinib under the current "off-label" rules which means getting the same drug under the name of Imbruvica I would cite the following research paper <nejm.org/doi/full/10.1056/N... and specifically the headings "Pharmacokinetic and Pharmacodynamic Measurements (not P and P Analyses), plus Discussion" This paper evaluates Ibru in a relapsed/refractory high risk CLL patient population which is a tougher group of CLLers to get good therapy results. The two mentioned section headings relates the bulk of the pertinent dosing information because it compares the patients who received 420mg daily to those taking 840mg daily. The second to last paragraph under the heading "Efficacy" is worth throwing in for the impressively high sustained percentages in cytopenia improvement. The key sentence in the next to the last paragraph of the section heading "Discussion" reads: "Greater than 90% occupancy of the pharmacodynamic probe and the similar response in the two dose groups provide support for the use of the 420-mg dose of Ibrutinib for relapsed CLL."

The good news is that the statistics for frontline treated patients who may not necessarily have high risk markers is even better than reports for the R&R patients in the above NEJM paper.

Another legitimate question may arise regarding proper dosing. As many already know and has recently been pointed out, therapeutic drugs are usually prescribed on a basis of mg and body mass "m2" or patient weight in "kg" i.e. Rituximab standard NHL dosing is at 375mg/m2. In the clinical trials there has been a set dose range of 420mg, 560mg, and 840mg daily per patient. The recommended dose of 420mg daily per patient is arrived at by gaging the dose necessary to occupy the critical site on the BTK to shut down the signaling that activates CLL to proliferate and accumulate in the LNs & BM (lymphnodes & bone marrow). Here is another paper abstract citing the observed amount of Ibrutinib relative to patient weight (2.5mg/kg) that is needed to achieve full occupancy or inhibition of BTK, the target of Ibru. <jco.ascopubs.org/content/31... I weigh approximately 160lbs or 72kg so I need at least 180mg Ibru per day to fully inhibit the target kinase, BTK. Paul Henderson recently posted that he, like I, was on a reduced dose of 280mg from the recommended 420mg because of a side effect. He said his weight was currently 184 but for the hell of it, let's assume he was so happy at his results on Ibrutinib that he ate enough steak and fries to get up to 190lbs. At that weight Paul would need a minimum of 215mg of daily Ibru to be effective. Paul might not want to get carried away by over eating but has a reasonable safety margin with 280mg Ibru daily at 190lbs. As Dr. Bryd told me on Feb. 3, 2014 "There is no reason at this time for a CLL patient to be on more than 420mg per day of Ibrutinib." Even if it is called Imbruvica - same drug in the same 140mg dose capsule!

Challenged by lbs to kg conversion?? calculate your minimum Ibrutinib dose and see if you need more than 420mg per day. <metric-conversions.org/weig... Up to about 340lbs of body weight the 3 cap per day totaling 420mg should be fine.

"Perseverance furthers" I-Ching

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[ThreeWs]

A patient on another forum recently calculated his dosing needs for Ibrutinib and wanted to know if he could take the lower dose of 280mg worried about side effects and encouraged by his bloodwork, my success at the lower dose and that of Paul Henderson. I am not a Doc and cannot give medical advice but here is my reasoned advice for staying with the 420mg dose.

My post on the rationale for Ibrutinib dosing at 420mg was aimed at helping those who might be denied the drug because they are being prescribed based on MCL not CLL at a higher dose of 560mg daily. Ibrutinib like all things CLL, is more complicated. Ibrutinib covalently binds irreversibly to a kinase other than its designed target kinase, BTK. This kinase is ITK or Interleukin-2 Inducible Kinase. This fact is important to answer your question because the function of inhibiting ITK is in potentiating Th1-based immune response. Th1 and CD8 T-cell response may actually play a significant role in the efficacy of Ibrutinib. <bloodjournal.hematologylibr... We are still in the learning phase of how best to use CLL targeting kinase inhibitors. To emphasize this ITK feature of Ibru inhibition, we see a rival drug CC-292 (formally Avila's BTK inhibitor AVL-292) not as active in early lower dose trials and it apparently does not inhibit ITK as does Ibru. Secondly, Ibru longterm side effects are unknown beyond about 4yrs but the safety profile in terms of side effects for that time is very good. Keep in mind that the side effects were similar for patient groups given 840mg as those on 420mg. Because we are all different, you want to have a margin of extra saturation with Ibru because your CLL is scrambling to find a signaling path around your blocked BTK. Thirdly, Dr. Jeff Sharman and other CLL experts postulate that the sooner one takes down the patient's tumor burden the less chance there is for the CLL to figure a way to come back. I am not sure this is so because we see patients react quickly to some chemo regimens only to relapse with more resistant disease and there is some speculation that maintaining a presence of an indolent clone population may be prophylactic in preventing a more dangerous clone from emerging so slow progress to various levels of remission may prove better until we figure out how to kill every last one of the little "B"s.

Remember that one cannot be in a CR by peripheral blood ALC alone. All three compartments of Blood, Lymphnodes and Bone Marrow must be examined and evaluated.

Happy for your great response - keep on the 420mg. until your Doc says otherwise. People have relapsed on Ibru. We don't want to hear you are one of them.

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