OPTIMIZATION OF THERAPEUTIC DOSES OF RADOTINIB FOR CHRONIC MYELOID LEUKEMIA BASED ON EXPOSURE-RESPONSE RELATIONSHIP ANALYSES
Author(s): ,
Hayeon Noh
Affiliations:
Department of Pharmacy,College of Pharmacy, Yonsei University,Incheon,Korea, Republic Of;Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University,Incheon,Korea, Republic Of
,
Min Soo Park
Affiliations:
Department of Pharmaceutical Medicine and Regulatory Science,Colleges of Medicine and Pharmacy, Yonsei University,Incheon,Korea, Republic Of;Department of Clinical Pharmacology,Severance Hospital, Yonsei University Health Systems,Seoul,Korea, Republic Of
,
Sung-Hyun Kim
Affiliations:
Department of Internal Medicine,Dong-A University Medical Center,Busan,Korea, Republic Of
,
Hari Menon
Affiliations:
Leukemia and Lymphoma Unit, Department of Medical Oncology,Tata Memorial Hospital,Mumbai,India
,
Saengsuree Jootar
Affiliations:
Department of Medicine,Ramathibodi Hospital, Mahidol University,Bangkok,Thailand
,
Tapan Saikia
Affiliations:
Department of Medical Oncology,Prince Aly Khan Hospital,Mumbai,India
,
Jae-Yong Kwak
Affiliations:
Department of Internal Medicine,Chonbuk National University Hospital,Jeonju,Korea, Republic Of
,
Joon Seong Park
Affiliations:
Department of Hematology-Oncology,Ajou University Hospital,Suwon,Korea, Republic Of
,
Hyeoung Joon Kim
Affiliations:
Department of Hematology-Oncology,Hwasun Hospital, Chonnam National University,Hwasun,Korea, Republic Of
,
Suk Joong Oh
Affiliations:
Deparment of Internal Medicine,Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine,Seoul,Korea, Republic Of
,
Hawk Kim
Affiliations:
Division of Hematology and Cellular Therapy,Ulsan University Hospital, University of Ulsan College of Medicine,Ulsan,Korea, Republic Of
,
Dae Young Zang
Affiliations:
Department of Hematology-Oncology,Hallym University Sacred Heart Hospital,Anyang,Korea, Republic Of
,
Sahee Park
Affiliations:
Cancer Research Institute, The Catholic University of Korea,Seoul,Korea, Republic Of
,
Hye Lin Park
Affiliations:
Central Research Institute,IL-YANG Pharm. Co., Ltd.,Yongin,Korea, Republic Of
,
Gong Yeal Lee
Affiliations:
Central Research Institute,IL-YANG Pharm. Co., Ltd.,Yongin,Korea, Republic Of
,
Dae Jin Cho
Affiliations:
Central Research Institute,IL-YANG Pharm. Co., Ltd.,Yongin,Korea, Republic Of
,
Jangik I. Lee
Affiliations:
Department of Pharmacy,College of Pharmacy, Yonsei University,Incheon,Korea, Republic Of;Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University,Incheon,Korea, Republic Of;Department of Pharmaceutical Medicine and Regulatory Sc
Dong-Wook Kim
Affiliations:
Department of Hematology,Seoul St. Mary's Hospital, The Catholic University of Korea,Seoul,Korea, Republic Of;Cancer Research Institute, The Catholic University of Korea,Seoul,Korea, Republic Of
EHA Library. Noh H. Jun 12, 2015; 100235; E1118 Disclosure(s): College of Pharmacy, Yonsei University
Department of Pharmacy
Ms. Hayeon Noh
Ms. Hayeon Noh
Contributions
Abstract
Abstract: E1118

Type: Eposter Presentation

Background
BCR-ABL1 tyrosine kinase inhibitors (TKIs) have been administered as fixed doses for adult patients with chronic myeloid leukemia (CML). However, due to the wide inter-individual variability in the pharmacokinetics of TKIs and increasing evidence supporting the relationship between drug exposure and the efficacy and toxicity of these agents, there may be potential benefits of TKI dose individualization based on body size. Radotinib is a selective second generation BCR-ABL1 TKI and a phase 2 study was previously conducted in patients with TKI failed CP CML.

Aims
Using the data from the phase 2 study, radotinib exposure-efficacy and -safety relationship analyses were conducted to explore the dosing methods that will potentially improve the efficacy and safety profiles of radotinib.

Methods

The efficacy and safety data were collected for 12 months after the initiation of radotinib therapy from a multi-center phase 2 study conducted in 77 CP CML patients resistant and/or intolerant to other TKIs. All patients received radotinib 400 mg twice daily until a dose-limiting toxicity (DLT) appeared, after which the dose was reduced to 300 mg twice daily. The relationships between the body weight-adjusted dose (Dose/wt) and the probability of achieving major cytogenetic response or experiencing DLT were explored using a logistic regression method. The analyses were repeated using body-surface-area-adjusted dose (Dose/BSA). Upon a stratification of the patients based on Dose/wt or Dose/BSA, time-to-first DLT curves were compared using a Kaplan-Meier method.



Results
Efficacy. No significant associations were found between radotinib Dose/wt or Dose/BSA and major cytogenetic response at Months 1, 3 and 6. Safety. Positive correlations were observed between radotinib Dose/wt and the probabilities of first DLT occurrence at Months 3 (p=0.002), 6 (p=0.003), 9 (p=0.004), and 12 (p=0.007). Similar positive correlations were observed for Dose/BSA. Statistically significant differences were evident in the Kaplan-Meier curves of DLT between various Dose/wt groups, particularly between the groups of Dose/wt <6 mg/kg and Dose/wt ≥6 mg/kg (p=0.008) with the median time to first DLT being 259 and 83 days, respectively. At the cut-off of 6 mg/kg, the patient weighs 66.7 kg. A 2-tier weight-based dosing method was recommended to reduce the probability of DLT: radotinib 300 mg or 400 mg twice daily for patients weighing ≤65 kg or >65 kg, respectively.

Summary

The probability of DLT increased without improvement in efficacy as the Dose/wt or Dose/BSA of radotinib increased. Therefore, a lower initial radotinib dose of 300 mg twice daily is recommended for CP CML patients weighing ≤65 kg. A randomized clinical trial would be needed to confirm the efficacy and safety of this alternative dosing regimen.



Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor

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