3 Discussion
Imatinib is a first generation BCR-ABL TKI, and has anti-leukemic
activity against CML. Treatment of CML has improved dramatically with
the development of TKIs, including imatinib. However, the
inter-individual variability in adverse events and clinical efficacy as
well as high drug cost remain major issues, and present a major obstacle
to treatment. There is also an issue of reduced efficacy and safety with
prolonged TKI administration. Therefore, TDM of TKIs is an important
tool for CML treatment. We have previously reported a case report of
successful determination of nilotinib dosage by TDM in a patient with
CML developing hepatic dysfunction.21 The safety and
efficacy of imatinib for CML have been reviewed.22Maintaining an optimal trough plasma imatinib concentration is important
for ensuring maximum efficacy in patients with CML.22However, there is few case reports of effective dose adjustment of
imatinib using TDM at the onset of adverse events. As one of the few
case reports, Shibuya et al., when imatinib was administered at 400
mg/day to CML associated with maintenance dialysis patients, the
Cmax was 2,600 ± 800 ng/mL in normal
subjects,23 but 4,950 ng/mL in dialysis patients was
calculated.16 In addition, the imatinib removal rate
by dialysis was as low as 6.3%, and it has been reported that blood
imatinib concentration increases gradually with continued administration
in dialysis patients and may reach a peak of 5,800 ng/mL, which is
considered to be the toxic level of imatinib.16Furthermore, imatinib is metabolized in the liver by cytochrome P450 3A4
(CYP3A4). Since there are reports that uremic substances can reduce
CYP3A4 activity in patients with chronic renal failure, caution should
be exercised in long-term use of drugs that are metabolized in the
liver.24,25 In this case, approximately one week after
resuming imatinib when dialysis was initiated for renal impairment, TDM
revealed that imatinib plasma level was within the therapeutic range
(1667 ng/mL). TDM performed one month after imatinib was resumed with
the patient on dialysis showed blood imatinib concentration of 2514
ng/mL, which was within the safe range. These results also support
previous report that the target trough concentration of imatinib is
1000-3000 ng/mL.22 After blood imatinib concentration
was confirmed by TDM, the physician decided to continue with the same
dose. Treatment was continued without any adverse effects such as
deterioration of renal function, and finally complete hematologic
response was achieved 43 days after resuming imatinib treatment. Thus,
TDM allowed maintenance of optimal plasma imatinib concentrations, which
not only prevented the occurrence of adverse events, but also maintained
clinical efficacy. This case report demonstrates successful
determination of imatinib dosage by TDM in a CML patient at initiation
of dialysis for acute renal dysfunction. TDM may provide useful marker
for individualized dosing of BCR-ABL TKIs in the treatment of CML.