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question about CYP3A4 inducers and inhibitors


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#1 Lucas

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Posted 12 January 2018 - 05:48 PM

Hey, guys. hope everybody's fine.

 

I always read that CYP3A4 inducers lead to less tki effectiveness and CYP3A4 inhibitors lead to more tki in the blood.

 

My question is: take some CYP3A4 inhibitor will make tki to be more effective or not? I'm asking that because from time to time somebody post here that was taking something that made the tki less effective and most of the time the "thing" is a CYP3A4 inhibitor.



#2 cmljax

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Posted 13 January 2018 - 08:08 AM

I know that I cannot have any grapefruit juice, which is a strong inhibitor of CYP3A4, is taboo for me.  I think the same holds true for Sprycel and Gleevec.  Taking an inhibitor reduces the metabolism of Tasigna, so instead of being metabolized, more of the drug enters the blood and stays in the body longer. The result: too much drug in your body. i.e. overdose. Inducers have the opposite effect. Read the prescribing info on your TKI carefully. I think you'll find that you want to stay away from this. 


Dx 9/26/16 WBC 28800; platelets 749; FISH 97% PCR 43%

Tasigna 600MG per day

October 2016                     PCR 22% IS

November 2016                 PCR 5.8% IS

December 2016                 PCR 0.1% IS  MMR!!

March 10, 2017                 PCR 0.006% IS  MR 4.22

Tasigna 450MG per day

April 5, 2017                      PCR <.003% IS

June 5, 2017                     PCR <.003% IS (dose reduction validated!!!)

Tasigna 300MG per day starting June 15, 2017

6-day drug break starting June 20, 2017 due to multiple AE's

July 24, 2017                     PCR <.003% IS

September 18, 2017          Negative, AKA PCRU

Tasigna 150mg per day starting 9/18/17

October 30, 2017               Negative

December 11, 2017           Negative


#3 Trey

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Posted 13 January 2018 - 10:57 PM

Early suggestions were that CYP3A4 was critical to Gleevec (and other) metabolism.  But later research showed CYP3A4 is not as significant in the body as lab testing had shown.  So overall CYP3A4 is a non-issue.

 

Eat more grapefruit.  It doesn't matter.

 

"Furthermore, our data indicate a high likelihood of autoinhibition of the CYP3A4-mediated metabolism of imatinib, leading to a less significant role for CYP3A4 in imatinib biotransformation than previously proposed."

https://www.ncbi.nlm...les/PMC3423228/



#4 cmljax

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Posted 14 January 2018 - 10:36 AM

I will defer to Trey on Gleevec, but please don't eat any grapefruit products at all if on Tasigna.  Peak levels of Tasigna can be increased as much as 60% if you do and that can exacerbate side effects up to an including and irregular heart beat caused by prolongation of the Qtc interval which can and has caused sudden death. The Qtc prolongation risk is a black box warning on Tasigna, so I doubt Novartis would have done this if they didn't suffer a few sudden deaths during the clinical trials.  If on Tasigna, it would be best to stay away from all inhibitors of CYP3A4.  Just my non-professional opinion based on what my oncologist told me and what I have read about my particular TKI.


Dx 9/26/16 WBC 28800; platelets 749; FISH 97% PCR 43%

Tasigna 600MG per day

October 2016                     PCR 22% IS

November 2016                 PCR 5.8% IS

December 2016                 PCR 0.1% IS  MMR!!

March 10, 2017                 PCR 0.006% IS  MR 4.22

Tasigna 450MG per day

April 5, 2017                      PCR <.003% IS

June 5, 2017                     PCR <.003% IS (dose reduction validated!!!)

Tasigna 300MG per day starting June 15, 2017

6-day drug break starting June 20, 2017 due to multiple AE's

July 24, 2017                     PCR <.003% IS

September 18, 2017          Negative, AKA PCRU

Tasigna 150mg per day starting 9/18/17

October 30, 2017               Negative

December 11, 2017           Negative





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