Fan Yang1, Li Zhang2, Xiao-Fan Zhu3, Wei Zhao4,5,6, Bei-Bei Zhao2, Jing-Liao Zhang2, Xi-Ting Liu1, Xue Li1, Bo-Hao Tang1, Yue Zhou1, Xin-Mei Yang7, John van den Anker8,9,10. 1. Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. 2. 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. 3. 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. 4. 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. 5. 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. zhao4wei2@hotmail.com. 6. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, No.44, Wenhua West Road, Jinan, Shandong, China. zhao4wei2@hotmail.com. 7. 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. 8. Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA. 9. Departments of Pediatrics, Pharmacology and Physiology, Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA. 10. Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland.
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/m2 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 (AUCss) of dasatinib 60 and 80 mg/m2 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 AUCss of dasatinib (80 mg/m2) 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.
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/m2 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 (AUCss) of dasatinib 60 and 80 mg/m2 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 AUCss of dasatinib (80 mg/m2) 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.