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Low Dasatinib Penetration of the Blood-Brain Barrier in Children With Philadelphia Chromosome-Positive Acute
Fangyuan Zheng1, Mingming Ding1, Aidong Lu1
1Department of Pediatrics, Peking University People's Hospital, Beijing, China.
Insights
Dasatinib shows poor penetration into the cerebrospinal fluid (CSF) of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), indicating limited blood-brain barrier passage despite therapeutic plasma levels.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Neuroscience
Background:
- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a challenging pediatric malignancy.
- Dasatinib is a tyrosine kinase inhibitor used in Ph+ ALL treatment.
- Understanding drug penetration into the central nervous system (CNS) is crucial for effective leukemia treatment in children.
Purpose of the Study:
- To measure dasatinib concentrations in paired plasma and cerebrospinal fluid (CSF) samples from pediatric patients with Ph+ ALL.
- To determine the extent of dasatinib blood-brain barrier (BBB) penetration in this population.
- To assess the relationship between systemic and CSF dasatinib levels.
Main Methods:
- Paired plasma and CSF samples were collected from 20 children with Ph+ ALL receiving oral dasatinib.
- A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was used to quantify dasatinib concentrations.
- The plasma-to-CSF concentration ratio was calculated to assess BBB penetration.
Main Results:
- Mean plasma dasatinib concentrations were 101.6 ± 42.1 ng/mL at 2 hours post-administration.
- Mean CSF dasatinib concentration was 0.5 ± 0.2 ng/mL at 2 hours.
- The median plasma-to-CSF concentration ratio was 225:1, indicating poor CSF penetration.
Conclusions:
- Dasatinib exhibits limited penetration into the CSF of children with Ph+ ALL.
- Despite achieving therapeutic systemic levels, dasatinib's efficacy in treating CNS leukemia may be constrained.
- Further research is needed to optimize CNS-directed therapies for pediatric Ph+ ALL.
Abstract:
We measured dasatinib concentrations in paired plasma and cerebrospinal fluid (CSF) samples from children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Blood samples were collected from children at 0 h (pre-dasatinib) and 2 h post-dasatinib, along with CSF. After validating a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for dasatinib in both matrices, we quantified drug concentrations in plasma and CSF and expressed blood-brain barrier penetration as the plasma-to-CSF concentration ratio. Twenty children with Ph+ ALL, who received oral dasatinib (60-80 mg/m2·day), were included in this study. The median age was 10.8 (5-16) years, with 13 males (65%) and 7 females (35%). In plasma, the mean dasatinib concentrations were 1.3 ± 0.7 ng/mL at 0 h and 101.6 ± 42.1 ng/mL at 2 h. In CSF, the mean dasatinib concentration was 0.5 ± 0.2 ng/mL at 2 h. The median paired plasma/CSF concentration ratio was 225:1 (98:1-406:1). In conclusion, despite therapeutic systemic levels, dasatinib penetrates poorly into CSF in children with Ph+ALL.
