This is an important topic that we have covered here many times. The CLL dosing of ibrutinib goes back to 2010. The original dosing of ibrutinib was arrived at through a series of FDA requirements and sensible dosing.
The phase I trial covered doses up to 12.5 mg/kg. No dose limiting toxicities were found. We found that everyone above 2.5 mg/kg had complete inhibition of BTK. Please note, ibrutinib inhibition probably needs to be >90% at all times to have a therapeutic impact. This is based upon the kids with X-linked agammaglboulinemia, who must have >85% loss of BTK before they have a deficiency and the fact that the mutation in BTK that leads to resistance is inhibited by ibrutinib, but only for short periods of time.
At the end of the phase I study, it was decided to move everyone to 560 mg daily as this provided what was believed to be adequate inhibition for everyone. We next did a trial comparing ibrutinib 420 mg daily versus 840 mg daily in CLL patients. This trial demonstrated the same response rates and no additional toxicities at the 840 mg dose and the dose was reduced for most patients thereafter to 420 mg daily. This comparison was a small number of patients studied for a short duration at 840 mg, but many of the patients remained on 840 mg daily long-term without complications. Thus, 420 mg daily was the CLL dose taken forward.
By this time, there was significant amounts of data in mantle cell patients using the patients from the phase I who were on 560 mg daily. These patients were put together into the filing for the FDA approval for mantle cell lymphoma. Given that the FDA only approves things based upon how studied, they approved 560 mg as the mantle cell dose, even though we knew the 420 mg and 560 mg doses were equivalent in patients. (Unless they weigh more than 200 kg.)
Given the above, and the fact that the greatest mistake would be to underdose a patient and loose benefit, the dosing recommendations for CLL were 420 mg daily, with dose reductions for toxicities. In my opinion, the only toxicities that are clearly dose related are likely to be thrombocytopenia, neutropenia, diarrhea, and joint aches. Thus, I start at 420 mg in order to make sure I am maximizing benefit and only dose reduce for toxicities.
I do recognize the stress of medication costs on patients. I just want to emphasize the importance of not taking chances with loosing benefit. The studies looking at lower doses make no sense to me. Why take a chance if you are tolerating the medication with a lower dose.
We have been speaking with the company regarding the ibrutinib tablets and the pricing. There are several reasons they priced them all the same, some “nice” reasons and some “selfish” reasons. The costs of manufacturing 280 mg, 420 mg, and 560 mg are all likely the same and very, very inexpensive. The costs of the medication are mostly due to the numerous unnecessary (and in one case), harmful, trials the FDA requires for approval. Did we need a trial testing ibrutinib versus chlorambucil (RESONATE2)? That trial was required by the FDA for full approval for ibrutinib, cost more than 52 million dollars, and lead to an increase risk of death in patients on the control arm, even with there being a cross over from the chlorambucil to ibrutinib. Thus we have a trial that added huge costs to the development of ibrutinib and harmed patients!
One problem that many of you might encounter is that the ibrutinib tablets have a different NDC (National Drug Code) and may be considered a new therapy by the insurances. This could lead to having to repeat copay windows and obtain approval all over again. Please try to look into this before you are switched in order to avoid an interruption of therapy. Pharmacyclics is looking into means for providing for “gap dosing” so no one misses doses, although many may already be experiencing this.
This is a crazy, nonsensical medical system we have. I didn’t vote for it. I struggle with it and in it every day. Nothing is more upsetting than seeing patients receive substandard therapy for any reason. I could have told you ibrutinib should have been approved and at 420 mg in 2012. Think about how many more people could have benefited instead of the delay in approval.
Rick Furman, MD