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

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.