Usage of therapeutic drug monitoring for estimate of patient compliance
to imatinib therapy.
Savelyeva M.I.1,
Eremenko N.N.1, Samoylova O.S.2, Samarina I.N.3,
Kascheeva N.E.2
1- “The First
Sechenov’s Moscow State Medical University, Moscow, Russia
2- Nijegorodsky
Regional Clinical Hospital, Nijny Novgorod, Russia
3- Dzerdjinsky
District Hospital, Dzerdjinsk, Nijegorodsky Region, Russia
For the first time on
the territory of the Russian Federation imatinib for treatment of chronic myeloid
leukemia (CML) in acceleration phase, blast crises and chronic phase as for the
front-line therapy or failure of interferon-α treatment used before, was
registered in 2001. The aim of CML therapy on the modern level is the
achievement of cytogenetic and molecular remissions. However, it is important not
only the fact of achievement of one or several endpoints – complete cytogenetic
response (CCyR), but also the period of time when this response is achieved [1].
Getting of complete cytogenetic and major molecular responses (CCyR, MMR) by 12
months of therapy guarantees 100% progression free survival (PFS) [1]. Such a result
is not possible for all CML patients. Imatinib resistance is a serious clinical
problem of CML treatment [2]. In spite of imatinib efficacy we sometimes
witness suboptimal response and failure of treatment [3]. Treatment success of tyrosine
kinase inhibitors mostly depends on the introduction of effective monitoring
system of treatment results that let doctors change therapeutic CML tactics in
time in each particular case. Imatinib resistance can have the primary character
(for example, phenotype specificities of HLADRB1*13(06) or HLА-DRB1*01 and HLА-DRB1*12(05) may be markers of fast CML progression
with death outcome) [4]. The
secondary resistance is losing effect upon positive treatment response [5]. It is
subdivided into true (that depends on pharmacodynamic (PD) and pharmacokinetic
(PK) distinctive features) and false. PD causes of the first rank are the
clonal proliferation of leukemia cells consisting point mutations in domain of
ABL-kinase [6]. PD causes of the second rank often arise as a result of
mutations that provocate conformation changes or change critically significant
tyrosine endings in imatinib binding regions of Bcr-Abl oncoprotein. [7]. PD
causes of the third rank are clonal progression connected with additional
chromosome abnormalities in cells with Ph(+) chromosome. PK causes imply the
decreasing of intracellular imatinib concentration that is conditioned by binding
plasma proteins; the decreasing of drug transport in cell and the increasing of
drug transport out of cell (because of hiper/hipoexpression of some transporters,
for example MDR1); the activation of kinases from Src family, such as Lyn [7,8].
In spite of the fact
that the therapeutic drug monitoring is not included in the monitoring system
of CML treatment approved ELN they have recently been discussing its usage to
estimate a patient’s compliance to imatinib [9]. For the first suboptimal compliance
of CML patients in accordance with imatinib therapy was mentioned in the work
of J.Tsang et al., 2006. From the 4043 CML patients total compliance (rate between
the dose taken and the dose, written down by the doctor) was 75% [9,10]. M. StCharles
identifies the fact that from the 340 CML
patients he revealed suboptimal compliance (% rate between the number of days
when the patient took the drug to the number of days of the follow up period) -
64 % [9,11]. Kutsev S.I. et al., 2009 found out the fact that break of imatinib
therapy more than 30 days during the first treatment year led to decreasing probability
of CCyR achievement after 12months of therapy in 2 times [9]. Later Kutsev S.I.
et al., 2010 showed that 48,5% of CML patients with suspicion of non compliance
to the treatment had minimal level of imatinib concentration less 1000 ng/ml [12]. Studying of mechanism
of imatinib resistance and improving the methods that solve this problem and
help to get more patients with total compliance are very important.
The study was located in Nijegorodsky Regional Clinical Hospital and
Dzerdjinsky District Hospital within the period of 2006-2010 years. The total
number of CML patients in Chronic Phase (CP) was 42. All of them had imatinib
in doses 300-800 mg once a day. 23 patients had treatment failure and 6
patients had suboptimal response. All of them had suspicion of non compliance.
There was the study of minimal plasma level concentration (Cmin) of
imatinib that was measured by HPLC/MS/MS method. The second measurement of
imatinib plasma level concentration performed after the talk with the patient
about importance of treatment compliance or doses escalation. After the first
measurement the median of concentration (Сmin) (ng/ml) from the patient who took imatinib in dose 300 mg/d
(n=1; 2,38%) was 1268 ng/ml. By the second measurement nobody took imatinib in
dose 300 mg/d. The median of Сmin from the patients with imatinib dose 400 mg/d (n=21; 50%) was – 1935 (range,
2 to 2521) ng/ml; after the second measurement it (n=17; 40,48%) was 1132,8 (range,
112 to 1885) ng/ml. The median of Сmin from the patients with imatinib dose 600 mg/d (n=16; 38,1%) was 2103,6
(range, 261 to 3530) ng/ml; after the second measurement it (n=21; 50%) was 1260,3
(range 410 to 2858) ng/ml. The median of Сmin from the patients with imatinib dose 800 mg/d (n =4; 9,52%) was 630,8 (range
215 to 1609) ng/ml; after the second measurement it (n=4; 9,52%) was 1495,3 (range,
402 to 2587) ng/ml.
In conclusion, the measurement of imatinib plasma level concentration is
an objective criterium of CML patient compliance.
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