Title

Population Pharmacokinetics and Safety of Dasatinib in Chinese Children with Core-Binding Factor Acute Myeloid Leukemia

Authors

Fan Yang, Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Li Zhang, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
Bei-Bei Zhao, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
Jing-Liao Zhang, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
Xi-Ting Liu, Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Xue Li, Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Bo-Hao Tang, Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Yue Zhou, Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Xin-Mei Yang, Department of Clinical Pharmacy, Clinical Trial Center, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China.
John van den Anker, Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA.
Xiao-Fan Zhu, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. xfzhu@ihcams.ac.cn.
Wei Zhao, Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. zhao4wei2@hotmail.com.

Document Type

Journal Article

Publication Date

1-1-2022

Journal

Clinical pharmacokinetics

Volume

61

Issue

1

DOI

10.1007/s40262-021-01054-6

Abstract

BACKGROUND: Dasatinib, an orally administered Src-family kinase inhibitor, is combined with the standard chemotherapeutic regimen to enhance antineoplastic activity against core-binding factor acute myeloid leukemia (CBF-AML) in adults; however, limited data are available for use in children. In the present study, we studied the pharmacokinetics and safety of dasatinib in children. METHODS: Dasatinib (60 or 80 mg/m once daily) was administered to 20 children with CBF-AML. Blood samples were collected and drug concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Population pharmacokinetic analysis and Monte-Carlo simulations were performed using NONMEM software, and safety analyses were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (NCT03844360). RESULTS: Twenty pediatric patients (3.3-14.4 years of age) were included, and a total of 40 dasatinib concentrations were available for population pharmacokinetic analysis. The mean (standard deviation) of the estimated area under the concentration-time curve extrapolated to steady state (AUC) of dasatinib 60 and 80 mg/m was 366.1 (146.6) ng·h/mL and 425.3 (150.7) ng·h/mL, respectively. The majority of adverse events were grade 1/2 in severity, including thrombocytopenia, rash, and pain in the extremities. The estimated cumulative incidence of complete remission and complete molecular response were 95.0% and 75.5%, respectively. CONCLUSIONS: The population pharmacokinetics of orally administered dasatinib were evaluated in pediatric CBF-AML patients. The AUC of dasatinib (80 mg/m) in CBF-AML pediatric patients was similar to those of dasatinib (100 mg) in adult patients. Dasatinib is well-tolerated in pediatric patients with CBF-AML.

Department

Pediatrics

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