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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.

Author information

1
Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, Korea.
2
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
3
Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
4
Chonbuk National University Medical School & Hospital, Jeonju, Korea.
5
Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.
6
Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
7
Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea.
8
Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin, Korea.
9
Department of Medicine, Dongsan Medical Center, Keimyung University, Daegu, Korea.
10
Seoul St. Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea.

Abstract

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.

KEYWORDS:

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

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