Understanding Ibrutinib and dosing rationale

[ThreeWs]

Dosing of Ibrutinib has come up for discussion on a number of forums and is on the minds of many patients. To further the discussion on this subject, Chris’s point is the most important – DIY custom dosing is foolish, potentially dangerous and in most cases unnecessary to avoid most side effects. Ibrutinib works great for the majority of patients. Dose reduction should be considered only under physician guidance in the face of persistent side effects. Most side effects from Ibru are experienced in the first 6 months and are transient.

I have been on Ibru for over 5 years and had to be dose reduced from 420mg to 280mg early in the Clinical Trial due to a rare eye problem now completely resolved. I have resolved all transient side effects i.e. diarrhea, angioedema, atrial fibrillation & atrial flutter except for brittle fingernails and possibly a drug related low platelet count (mid 80s).

Here are a bit of interesting facts about Ibrutinib. Early Trials took varied dosing up to 840mg with no discernible side effect differences from lower doses. The ideal goal for Ibrutinib is to block the target kinase (BTK) from allowing the signal from the BCR (B cell receptor) to facilitate proliferation and adhesion/homing activity of the CLL cancer cells. The inhibition of BTK is ideally at 100% but considered adequate at >90%. To do that it was determined that a minimum dosing would be 2.5mg per kg of patient weight so technically, yes one could make a case for lower dosing based on low weight patients but we all METABOLIZE drugs differently and because Ibru inhibits several other important kinases in addition to BTK our side effects can vary in the extreme. Attempts to lower dosing may vary the ability to keep the CLL Bear in hibernation. CK (Complex Karyotype) and the more dangerous clones of 17p- & 11q- have a higher and quicker relapse rate than other phenotypes of CLL making optimal dosing standard for every individual difficult to precisely measure.

While taking Ibru, mutations may occur as our CLL Bear tries to resume dancing with us. Two most common mutations resulting in relapse are found in the BTK itself (c481s) and in a downstream signaling pathway locus of PLCgamma2. It is in the interest of keeping these mutations from occurring that Ibrutinib be taken every day and at the prescribed level of margin (420mg) that is most likely to prevent these mutations from happening, although I have not seen any proof that the mechanism for mutations leading to relapse are enhanced by noncompliance or lower dosing.

At OSU where I am treated and has the most experience with Ibru, I have been told that there have not been any relapses in patients without the dangerous clones of 17p-, 11q-, containing p53 defects or CK (Complex Karyotype). This may reflect compliance, dosing adherence and lack of prior chemo based treatments.

Good paper though somewhat dated on Ibrutinib in the Relapsed patient setting. nejm.org/doi/full/10.1056/n...

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