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Precision dosing using concentration-controlled dosing of TKIs for CML could maximize the clinical benefit and minimize toxicity

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This makes a lot of sense to me.  I wonder if it will ever become a standard practice in the treatment for CML?

 

[Management using the plasma concentration of tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia: an update].
[Article in Japanese]
Miura M1, Takahashi N2.
Author information

1     Department of Pharmacy, Akita University Hospital.
2     Department of Hematology Nephrology and Rheumatology, Akita University Graduate School of Medicine.

Abstract

Imatinib, nilotinib, dasatinib, bosutinib, and ponatinib are tyrosine kinase inhibitors used to treat chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and target concentration intervention (TCI) are novel strategies that use concentration-controlled dosing (CCD) to attain a faster and more profound clinical response in patients with CML. The target plasma trough concentration (C0) of imatinib is 1,000 ng/ml to obtain a higher major molecular response (MMR) rate. Target nilotinib and bosutinib C0 of 900 and 62 ng/ml, respectively, are recommended to attain a better response, whereas a target ponatinib C0 of 21.3 ng/ml has been proposed to obtain a better response and decrease the risk of adverse events, such as vascular toxicity. Approaches for these four TKIs involve the use of TCI with specific target concentrations rather than TDM with a therapeutic range. Conversely, for dasatinib, a lower C0 of <4.33 ng/ml is the maximum toxic concentration recommended to avoid pleural effusion. Therefore, precision dosing using CCD of TKIs for CML could maximize the clinical benefit and minimize toxicity.

KEYWORDS: Target concentration intervention; Therapeutic drug monitoring; Tyrosine kinase inhibitor

PMID:     31597837
DOI:     10.11406/rinketsu.60.1140

Seems like “common sense”, but I imagine it’s a lot harder to manage a large number of patients in a clinic environment like this. 

I now here in the UK this is sometimes done, but only when there is a specific need (such as a patient not responding as expected, or getting more severe side effects). For the rest of us, it’s more of a hit and hope and adjust if things are going bad.

David.

I would like to think our doctors could use this information to provide us with better care.  Especially if it could reduce our chances of experiencing these adverse reactions:

 

    bleeding which can be serious and may lead to death

    blood clots or blockage in your blood vessels may lead to heart attack, stroke, or death

    heart problems, including heart failure which can be serious and may lead to death

    liver problems, including liver failure, which can be severe and may lead to death

    skin rash,
    abdominal or stomach pain,
    tiredness,
    headache,
    dry skin,
    constipation,
    fever,
    joint pain, or
    nausea

    chest pain or heavy feeling,
    pain spreading to the arm or shoulder;
    sudden numbness or weakness (especially on one side of the body),
    problems with vision, speech, or balance;
    sudden cough, rapid breathing, coughing up blood;
    easy bruising, unusual bleeding;
    confusion, severe drowsiness, feeling like you might pass out;
    fever, chills, flu symptoms, sores in your mouth and throat;
    irregular heart rate;
    shortness of breath (even with mild exertion);
    yellowing skin or eyes;
    severe pain in your upper stomach spreading to your back;
    little or no urinating,
    numbness or tingly feeling around your mouth,
    overactive reflexes,
    weak pulse,
    fainting; or
    dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, seizure).

I asked  a question about therapeutic drug monitoring at last year's patient day, in I think the last Q&A session. Through my work some years earlier in toxicology I was aware of work done by Prof Flanagan's team at KCH who had developed a methodology for measuring serum levels of imatinib, and shown a huge variation in levels across a population of over 100 patients. I asked about its clinical use. The view from the panel was that it might be used in patients whose body weight was outside the normal range, and one ethnic group (sorry I can't remember which one) whose metabolism is different from the original patients in the trials. Other than that the criticality of taking the blood sample at exactly peak or trough levels is the over-arching factor. The timing of the sampling in relation to taking the daily dose makes it too complicated to use clinically, because half life is short. It still seems to me (talking imatinib here) that those with really bad side effects might have a high serum level, and those responding slowly might have a lower level, but there was no enthusiasm from the clinicians to pursue this.  

Thanks Alastair,  I had the plasma level checked once when I was taking 200mg/day.  I guess my result was pretty much in line with the dose.  Here's the result from that test:

 

Comments from the Doctor's Office:  Your lab results indicate an excellent response to treatment.  We should repeat your lab testing in 3 months.  Your imatinib level is on the low side, but this is consistent with the lower than normal dose that you are taking.

Study Result
Narrative

Imatinib levels over 1000 ng/mL are associated with a higher likelihood of achieving a major molecular response. See literature for additional detail.

Larson RA, et al. Blood 2008;111:4022-8.

Guilhot F, et al. Haematologica 2012;97:731-8.

Testing performed using mass spectrometry. This is a lab-developed test and not evaluated by the FDA.

Component                        Your Value        Standard Range

IMATINIB, PLASMA       506 ng/mL        500 to 1,999 ng/mL500 - 1,999 ng/mL

IMATINIB DOSE 200 mg 
DATE/TIME OF LAST DOSE 6-19-2016 at 2000 hours (8 PM) 
General Information

Collected on 06/20/2016 3:08 PM from Blood (Blood)

Resulted on 06/23/2016 1:11 PM

Interesting.  I had quite a few side effects on the nilotinib, was switched to dasatinib after 2 months, and after 2 months on that my dose was lowered to 50 mg due to side effects.  I'd gotten so lightheaded among other things I could no longer drive safely.  I've also had very rapid response measured both in my blood counts and the BCR-ABL1 test.  I just got my first BCR-ABL1 test last week and was wondering if perhaps with both good and bad reactions to the drugs being greater than normal maybe my system ends up with more of it in my blood stream.  I am a fairly small person.

Hi

This is the link to Prof Flanagan's team's paper on Pubmed.