IM serum momitoring

[Guest guest]

Hi, friends.

I’m going to begin discussing abstracts from the most interesting CML-related

“poster sessions†at ASH. Ideally I would group these by topic, but I’m

not that organized so I’ll take them as I found them.

I’ve posted the first abstract below in its entirety. As I go along I’ll

see whether or not this format makes sense.

These authors are seriously French (note the term “lymphoblatique leukemiaâ€

– though I only wish my French was as good as their English), so I had a bit

of interpreting to do. If I understand them correctly, it appears that they may

have come up with a reliable method for measuring serum levels of IM (Gleevec).

This is important because, Novartis’ assurances to the contrary, it’s not

true that “one dose fits all.†It’s quite likely that some cases of

apparent IM resistance are really due to patients’ failure (for whatever

reason) to achieve adequate serum levels if the drug, while others have to stop

or reduce their IM intake due to toxicity. It would be nice to know who has

levels that are too high or to low so we we can adjust the dose without risk of

resistance or toxicity. For reasons known only to themselves, Novartis has

refused to release their method for ascertaining serum levels from the start, so

it’s nice that others are developing alternatives.

Interestingly, five patients in this study who had had less than ideal

responses were found to have low blood levels of IM. There were pretty

straightforward reasons for this in every case, and once the problem was

recognized they were probably quite easily corrected (though the authors don’t

say so). Three of them were on seizure medicines which increased the rate of

metabolism of IM – which reminds me that several years ago a patient on

Rob’s list found themselves in a similar boat; it was with considerable

satisfaction that we, the amateurs, the patients, helped them figure out the

problem and correct it.

The technique used here for measuring IM level seems pretty esoteric to me

(it’s the same as is used in astrophysics for measuring the composition of

stars, if I remember correctly). I’d rather Novartis would just release their

method to commercial labs so we could all use it. Oh well, maybe someday…

Regards,

Rockefeller

______________________

[1995] Quantification of Imatinib in Human Plasma by High Performance Liquid

Chromatography-Tandem Mass Spectrometry: Applications to Therapeutic Drug

Monitoring of Patients with Chronic Myelogenous Leukemia. Session Type: Poster

Session 199-II

Francois-Xavier Mahon, Stéphane Picard, Karine Titier, Franck Nicolini,

Dominique Ducint, Nicolas , Gerald Marit, Patrice Berthaud, Mathieu

Molimard . Hématologie, Maladie du Sang, CHU de Bordeaux, Bordeaux, France;

Laboratoite de Pharmacologie et de Toxicologie, CHU de Bordeaux, Bordeaux,

France; Service d'Hématologie Clinique, Hôpital Edouard Herriot, Lyon, France;

Novartis Pharma, Rueil Malmaison Cedex, France

Imatinib (Gleevec® or Glivec®) is a competitive inhibitor of protein tyrosine

kinase is currently used for the treatment of chronic myeloid leukaemia (CML),

Philadelphia chromosome-positive acute lymphoblatique leukemia and for other

malignant pathologies.

Although there is no clearly defined therapeutic window, the imatinib plasma

quantification seems interesting to evaluate patient compliance to daily oral

therapy, drug-drug interactions or pharmacokinetic/pharmacodynamic relationship.

The aim of this study was to develop a simple and accurate liquid

chromatography-tandem mass spectrometry (LC-MS/MS) method for the imatinib

quantification, adapted to routine applications. After a liquid-liquid

extraction, the imatinib and its deuterated internal standard were eluted on a

XTerra® RP18 column with a gradient of acetonitrile-ammonium formiate buffer 4

mM pH 3.2. Imatinib was detected by electrospray ionisation mass spectrometry

with multiple reaction monitoring mode. The calibration curves were linear over

the range 10-5000 ng/ml. The limit of quantitation was set at 10 ng/ml. The bias

was lower than 8 %. Intra-day and inter-day precisions were lower than 8 %. The

extraction recovery was higher than 90 %.

The monitored population was defined as follows: patients treated for CML and

receiving imatinib with one daily dose of 300, 400 or 600 mg. Blood samples were

collected at steady state, 23 (±3) hours after drug administration, and were

centrifuged at 4500 rpm for 5min. As shown on the figure 1, all patients treated

with 600mg have a concentration more than 500 ng/ml which corresponds to the

efficient concentration of imatinib according to the previously in vitro studies

(i.e. the target plasma concentration required to induce the death of leukemic

cells). Five patients – previously known as not having an efficient

hematologic response or cytogenetic response showed an imatinib level lower than

500 ng/ml. Two of these patients were not compliant and three patients were

coadministered with enzymatic inducers: phenytoïn or phenobarbital or

oxcarbazepine.

This method is simple, adapted to routine application and allows accurate

therapeutic monitoring of imatinib. It can be used to evaluate patient adherence

to daily oral therapy, drug-drug interactions or pharmacokinetic/pharmacodynamic

relationship. In conclusion, regarding the definition imatinib resistance in

CML, it seems necessary to take in account the value of the imatinib

concentration. A study of correlation with the cytogenetic and molecular

response is in progress.