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Cancer Med. 2018 May;7(5):1766-1773. doi: 10.1002/cam4.1436. Epub 2018 Mar 25.

Determination of a radotinib dosage regimen based on dose-response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia.

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Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, Korea.
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Chonbuk National University Medical School & Hospital, Jeonju, Korea.
Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.
Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea.
Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin, Korea.
Department of Medicine, Dongsan Medical Center, Keimyung University, Daegu, Korea.
Seoul St. Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea.


Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP-CML, the dose-efficacy as well as dose-safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose-limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR-ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12-month follow-up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long-term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP-CML.


Chronic myeloid leukemia; dose determination; dose-response relationship; radotinib; tyrosine kinase inhibitor

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