IM serum momitoring

[Guest guest]

I sent this post previously, when I was at ASH, but it came through really

garbled, so I'm sending it again because it's quite an important one:

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I¹m going to begin discussing abstracts from the most interesting

CML-related ³poster sessions² at ASH. Ideally I would group these by topic,

but I¹m not that organized so I¹ll take them as I found them.

I¹ve posted the first abstract below in its entirety. As I go along I¹ll

see whether or not this format makes sense.

These authors are seriously French (note the term ³lymphoblatique leukemia²

­ 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, Novartis¹ assurances to the contrary,

it¹s not true that ³one dose fits all.² It¹s quite likely that some cases of

apparent IM resistance are really due to patients¹ 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 it¹s 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

don¹t 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 Rob¹s 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

(it¹s the same as is used in astrophysics for measuring the composition of

stars, if I remember correctly). I¹d rather Novartis would just release

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

somedayŠ

Regards,

R

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[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.