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.