Sunday, May 17, 2015

Take your pills - ibrutinib dosing matters!

When we are investigating new drugs that have never been tested before, we start with what's called a phase 1 study.  Historically, the goal of a phase 1 study was to define the "maximum tolerated dose." In the era of traditional cytotoxic chemotherapy, you knew you had arrived at that dose when patients simply couldn't handle any more - it was just to much. Perhaps they had too much nausea or vomiting, or the liver couldn't handle it anymore, kidneys failed, or some other toxicity made it clear that you had reached the limits of human tolerance.  As researchers, we just hoped we could get the drug levels high enough without causing too much damage.  If we achieved blood levels that we expected to kill the cancer cells without irreparably harming the patient in the process - that was victory.

Many of the new drugs challenge that paradigm.  When treatments effectively target the specific molecular abnormality with a cancer cell we can see considerably more efficacy while at the same time reducing toxicity.  This has led to the concept of "optimal biologic dose."  Instead of pushing the dose to the max, you only increase the dose as far as you need to - often with substantially less side effects than the traditional therapies.

Unfortunately, "optimal biologic dose" is much harder to define than "maximum tolerated dose."  It presumes that we have effective and accurate means of actually measuring what were trying to do.  While it may come as a surprise to many patients, the unfortunate reality is that there is an enormous amount of human judgment as well as a paucity of clear data involved in early clinical trials. Things are not as scientifically certain in early trials compared to the level of data we have later in a drugs like cycle.  Furthermore, we often need to generalize to the larger population from a very small subset of patients that are appropriate for a phase I study.

There is new data regarding the dosing of Ibrutinib that I think is really important to consider.

Most drugs inhibit enzymes in what we call a "reversible" fashion.  This means that the particular target is turned off only when you have high enough levels of the drug in the blood.  Ibrutinib is a little bit different, it is what we call a "covalent" inhibitor.  When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body.  Within just a few hours of taking a pill there is virtually no free drug in the blood.  Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK.  This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.

When you had a sore throat as a kid, the doctor always said to be sure to take all your pills so that the bacteria didn't become resistant.  It is virtually a scientific paradigm that exposing bacteria to inadequate antibiotic dosing creates resistance.  The same is probably true in leukemia and lymphoma with some of the new drugs.  A CLL cell that has its B-cell receptor signaling pathway completely inhibited has a hard time escaping that inhibition.  If that same pathway is only partially inhibited however, it will try to find ways to escape.   This is why the discovery of mutations in the BTK protein that confer resistance to Ibrutinib or so important. These can only arise in cells that have survived the BTK inhibitor long enough to figure out how to thrive under the suppressive influences of Ibrutinib.

Dose intensity can be measured in two key ways.  The first is how many days you take it out of how many days you are supposed to take it.  We already know in other chronic leukemias like CML, adherence to Gleevec (imatinib) is the biggest predictor of treatment success.  Heck, it is even true in breast cancer with hormonal agents.  Now it looks like the same is true in CLL.  Sometimes side effects force you to hold therapy - but prolonged drug holds are undesirable.  Patients who had drug holds in excess of 8 days were almost three times more likely to experience a disease progression (link to ASCO 2015 abstract here).  

The second way dose intensity is measured reflects what dose you take daily compared to the "optimal biologic dose."  There was a very compelling presentation at AACR a few months ago  (I am still trying to figure out how to link to the actual poster, but here is link to the session).  The study title was "Population Pharmacokinetic-Pharmacodynamic (PKPD) Modeling of Ibrutinib in Subjects With B-Cell Malignancies" by Poggesi et al. (prize to the first person who figures out how to find the actual poster).  I need to get a little technical for a minute - stick with me.

As I wrote above, ibrutinib has a cool property that is unique compared to most drugs.  Since it covalently (or irreversibly) binds to BTK, we can do a blood draw, isolate the CLL cells, purify the BTK protein, and look to see how many molecules of the BTK protein are "bound" to a molecule of ibrutinib.  This is what we call, "receptor occupancy."  The higher the occupancy, the more drug is bound to the protein, and the more the pathway is shut off.

You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses.  If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective.  96% of patients achieve that level of occupancy at any of those doses.  that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off."  It is more like a dimmer switch on the lights instead of an on/off.  75% occupied means that there is a lot of room for cells to try to discover ways to become resistant.  If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking on pill.  In short - dose matters.  You get more complete pathway inhibition with higher doses of ibrutinib.

What we don't really know what level of pathway inhibition is optimal for CLL treatment.  It is tempting to think that 100% occupancy in 100% of subjects might be much better at preventing eventual resistance - but honestly, we do not know if that might mean higher levels of side effects. How could we get there?  Well, perhaps we didn't actually define the "optimal biologic dose" correctly in the original phase I study.  We pretty much stopped escalating dose because it seemed to be doing what we wanted it to do in the relatively small population of patients we were studying.

I would be curious to go back and do a "dose optimization" study to see if we could modify either the dosing schedule or the actual dose taken to see if we could make ibrutinib work better than it already does.  I also worked on another BTK inhibitor that is no longer in development called CC-292.  We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily. Other BTK programs are looking at this as well.  Another way of potentially addressing such drug limitations is by adding a second drug that acts through different mechanisms.  This should ONLY be done in the context of a research study.  We have three such studies within the US Oncology network of sites (and here as well) including the addition of ublituximab (an updated version of rituximab), the combination of a BTK and PI3K inhibitor, or even BTK in combination with one of the new immune checkpoint inhibitors - pembrolizumab. 

Doctors tend to reduce doses when there are problems.  It is how we think about so many different clinical problems, that we tend to assume it is smart decision making.  In my own patients, I am concerned that dose reductions or prolonged dose interruptions may be causing ibrutinib to be less effective than if we can maintain the dose intensity.

To leave a comment, click on the title of this blog post.  It will open up the blog post in a separate window with a comment field at the bottom.  All comments are reviewed by myself before being allowed to be posted - be patient, I'm a busy guy.

Thanks for reading.


  1. Dr. Sharman,

    Can you please speak to your understanding of aggressive progression for patients who discontinue ibrutinib, and how this may or may not be a function of dose adherence as discussed above?

    1. Several "kinase inhibitors" in several different diseases are associated with a "rebound syndrome" after discontinuation. When I stop either ibrutinib or idelalisib, I try to keep pt on drug until next therapy ready to go or give a course of steroids.

    2. I am doubtful that this is coming soon. Makes reasonable sense. We do similar things in HIV. Works best when the two drugs work at different locations of the same enzyme. The Acerta compound and the Gilead compound (from ONO). and the Celgene compound (CC-292) all bind at Cys481 so unlikely those would be combined. Maybe other BTK inhibitors out there targeting other locations (I'm aware of at least one). More likely, it will be combinations with other good targets such as Syk, PI3K, BCL2, CD20, PD-1 or others - but ONLY in context of clinical trials for now. Do not do this on your own.

  2. Thanks for this informative article and - in general - for your blog! It's very readable and understandable to non-medical professionals and patients (I'm an MCL survivor... at least for now!). Namaste...

  3. Dr. Sharman,

    I am very appreciative of all the great work you are doing and taking the time to write your blog is amazing. I was recently diagnosed with CLL and your blog has really helped me to better grasp what I am (and will be) dealing with.

    Here is a possible link to the poster (if it helps):

    Thanks again!

  4. Great item. I have been on Ibrutinib for 15 months now and my numbers are near normal. Chemo is not for me! I am 11q with skin cancer issues that concern my local oncologist. I'm trying to make him understand that my skin cancer issues go back to the 1980's. I grew up in the Miami, Florida area and spent all summer at the community pool. I also lived in Hawaii for six years sailing, swimming, golfing jogging, etc. My local oncologist is concerned that Ibrutinib is causing my skin cancer. Hopefully items such as yours will calm him down.

  5. Im having a hard time understanding how resistance could form since there is an irreversible bond being formed between the cells and the medication. In my mind every cell that is affected by ibrutinib is "turned off" and all other cells not reached by that dose are not affected. It seems like its all or none and there is no partial response allowing cells to adapt.

    An issue along the same vein comes to mind when my father was taken off of his regular dose of ibrutinib because he was given an antifungal (voriconazle) that was said to inhibit its metabolism. In my mind , if most the medication is binding to cells than I would think that its actual metabolism wouldnt be much of an issue since its now bonded to a cell and wouldnt go through its normal metabolic pathway.

    1. CLL cells are continuously producing new BTK protein. Furthermore, not every single BTK protein is shut off in every single cell. Think of it more like a light dimmer instead of an on/off switch.

  6. I'm currently on Ibrutinib 420 mg/day for about six months so far. In regards to my CLL it's worked brilliantly to shrink nodes/spleen to normal, and my counts never went far out of normal range either. Side effects I ascribe to Ibrutinib are broken capillaries in my skin at various spots, fragile finger nails, skin cracking at my fingertips, and (this one isn't bad) curly hair!

    "When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body. Within just a few hours of taking a pill there is virtually no free drug in the blood."

    Given the rapid clearing, why isn't it better to take 140 mg every 8 hours, rather than
    all 420 mg at once each 24 hours?


    1. Agree- interesting scientific question but currently no evidence to support doing this.

  7. Do you think that someday there might be a rationale to use 2 different BTK inhibitors at the same time, if they both work as single agents but have different binding sites (since BTK inhibition works and side effects appear to be manageable, but 1 BTK inhibitor doesn't inhibit 100% of BTK)? Thanks!

  8. Dr Sharman, do you think the effects of dose reduction as described in your blog would be the same for CML where the suggested dosage of Ibrutinib is 560mg (4 tablets)? Why does it need to be a higher dose to begin with!

  9. This dosing point raises the concern for patients having to stop ibrutinib for minor surgery (3 days before and 3 days after) or longer periods for major surgery. This would seem to increase the chances for a relapse. Not holding the drug for surgery presumably may have its own problems but has this in fact been established or is the holding based on concerns for what might happen? Seems to leave the patient between a rock and a hard place.


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