title: Optimization of radotinib doses for the treatment of Asian patients with chronic myelogenous leukemia based on dose-response relationship analyses.
abstract: A fixed dose regimen for tyrosine kinase inhibitors (TKIs) is postulated to be responsible for variable safety outcomes in the treatment of chronic myelogenous leukemia (CML). The objective of this study was to explore an optimal dosing regimen for a TKI, radotinib, to improve its safety profile. Clinical data were obtained from a Phase 2 study of fixed-dose radotinib in 77 Asian patients with CML. The magnitude of radotinib dose adjusted for patient's body weight (Dose/BW) and the probability of dose-limiting toxicity (DLT) demonstrated a positive association (Logit[P] = 0.86*[Dose/BW]-4.45, p = 0.001). There was a significant difference in the Kaplan-Meier curves for time to first DLT between the patient subgroups of Dose/BW <6 and ≥6 mg/kg (259 versus 83 days). Consequently, a two-tier weight-based dosing regimen may improve the safety of radotinib: 300 mg or 400 mg twice daily for patients weighing ≤65 or >65 kg, respectively.
authors.affiliation: a Department of Pharmacy, College of Pharmacy , Yonsei University , Incheon , Republic of Korea ;|b Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy , Yonsei University , Incheon , Republic of Korea ;
authors.forename: Hayeon
authors.initials: H
authors.lastname: Noh
authors.affiliation: c Department of Pharmaceutical Medicine and Regulatory Science, Colleges of Medicine and Pharmacy , Yonsei University , Incheon , Republic of Korea ;|d Department of Clinical Pharmacology, Severance Hospital , Yonsei University Health Systems , Seoul , Republic of Korea ;
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Park
authors.affiliation: e Department of Hematology and Oncology , Dong-A University Medical Center , Busan , Republic of Korea ;
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: f Department of Internal Medicine, Kangbuk Samsung Hospital , Sungkyunkwan University School of Medicine , Seoul , Republic of Korea ;
authors.forename: Suk Joong
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: g Department of Internal Medicine , Hallym University Sacred Heart Hospital , Anyang , Republic of Korea ;
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Zang
authors.affiliation: h Central Research Institute , IL-YANG Pharm. Co., Ltd. , Yongin , Republic of Korea ;
authors.forename: Hye Lin
authors.initials: HL
authors.lastname: Park
authors.affiliation: h Central Research Institute , IL-YANG Pharm. Co., Ltd. , Yongin , Republic of Korea ;
authors.forename: Dae Jin
authors.initials: DJ
authors.lastname: Cho
authors.affiliation: i Cancer Research Institute , The Catholic University of Korea , Seoul , Republic of Korea ;|j Department of Hematology, Seoul St. Mary's Hospital , The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: a Department of Pharmacy, College of Pharmacy , Yonsei University , Incheon , Republic of Korea ;|b Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy , Yonsei University , Incheon , Republic of Korea ;|c Department of Pharmaceutical Medicine and Regulatory Science, Colleges of Medicine and Pharmacy , Yonsei University , Incheon , Republic of Korea ;|d Department of Clinical Pharmacology, Severance Hospital , Yonsei University Health Systems , Seoul , Republic of Korea ;
authors.forename: Jangik I
authors.initials: JI
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044466:Asian People; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001830:Body Surface Area; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000606751:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl)-3-(4-pyrazin-2-ylpyrimidin-2-ylamino)benzamide; D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Radotinib; chronic myelogenous leukemia; dose optimization; dose-response relationship; tyrosine kinase inhibitor; weight-based dosing