Pharmacokinetics of nilotinib in imatinib‐resistant/intolerant chronic myeloid leukemia patients on hemodialysis for chronic renal failure
Authors: Takashi Onaka, Naoto Takahashi, Masatomo Miura, Akihito Yonezawa, Kazunori Imada, Kenichi Sawada
Journal: American Journal of Hematology (2012)

To the editor: Nilotinib is a second-generation tyrosine kinase inhibitor used to treat patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML). The safety and efficacy of nilotinib are well established [1]; however, very little data is available for patients with end-stage renal disease. Here, we report successful treatment of three CML patients on maintenance hemodialysis (HD) for chronic renal failure (CRF). To evaluate the pharmacokinetics of nilotinib in patients on HD, plasma nilotinib levels were determined by high-performance liquid chromatography [2]. In 2008, a 46-year-old woman on maintenance HD for polycystic kidney disease was diagnosed as Philadelphia-positive CML chronic-phase and initially administrated imatinib 300-mg QD. Although plasma imatinib levels reached 1,400 ng/ml and no ABL point mutations were detected, a major molecular response (MMR) was not achieved after 2 years of imatinib treatment. She was therefore switched to nilotinib 200 mg BID. The only adverse event was grade-2 muscle pain, and a MMR was achieved 6 months after switching to nilotinib. In 2007, a 61-year-old man on HD for CRF was diagnosed with CML chronic-phase and was started on imatinib 200-mg QD. A complete cytogenetic response was achieved in 12 months, but he was forced to stop imatinib after developing interstitial pneumonia and gastric bleeding. He was then switched to nilotinib 200-mg BID. One month later, the nilotinib treatment had to be interrupted due to QT interval prolongation, and reduction of the dose to 200-mg QD was necessary to resolve this adverse event. Nonetheless, a MMR was achieved 8 months after switching to nilotinib. In 2010, a 78-year-old woman on HD for diabetic nephropathy was diagnosed with CML chronic-phase and started on imatinib 400-mg QD. After 3 months, the imatinib was discontinued due to nausea and vomiting that persisted even though she received adequate supportive care. She was then switched to nilotinib 200-mg BID. The nilotinib also caused nausea initially, but it gradually disappeared, enabling the patient to continue taking the drug without a dose reduction. A MMR was achieved 3 months after switching to nilotinib. There were no significant differences between the plasma nilotinib concentrations before and after HD in the three patients described above (P = 1.0000, Wilcoxon signed-rank test, Table 1). This suggests that nilotinib in plasma is not cleared by HD, nor are the pharmacokinetics of nilotinib influenced by HD. Moreover, the dose-adjusted AUCs for nilotinib in patients on HD are similar to those previously observed in a Japanese Phase I/II study [3]. Our results indicate that the pharmacokinetics of nilotinib likely do not change in patients on HD for end-stage renal disease. Thus, although we reduced the dosage of nilotinib to prevent unexpected adverse events in one of these three patients, our findings indicate that, as with imatinib [4, 5], the standard dose of nilotinib can be safely administered to patients on HD with renal failure at any stage. Takashi Onaka*, Naoto Takahashi , Masatomo Miura , Akihito Yonezawa*, Kazunori Imada*, Kenichi Sawada , * Department of Hematology, Kokura Memorial Hospital, Kitakyushu, Japan, Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan, Department of Pharmacy, Akita University Hospital, Akita, Japan.