Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients

by Selleckchem | Jul 15 2023

Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.

Comments:

The passage you provided discusses the infiltration of malignant cells into the central nervous system (CNS) in hematological malignancies and the limited investigations on the penetration of venetoclax, a medication, into the CNS. It reports the results of a Phase 1 study conducted in pediatric patients with relapsed or refractory malignancies, focusing on venetoclax's ability to cross into the CNS.

The study analyzed venetoclax levels in both plasma and cerebrospinal fluid (CSF) samples. Venetoclax was detected in CSF samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL). The plasma:CSF ratio, which indicates the relative concentration of venetoclax in plasma versus CSF, ranged from 44 to 1559 (mean, 385). Interestingly, there were no significant differences in plasma:CSF ratios between patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and no clear trend was observed in the ratios over the course of treatment.

Furthermore, the study observed an improvement in the central nervous system involvement status in patients who had measurable concentrations of venetoclax in the CSF. The resolution of CNS complications was observed for up to six months while the patients were on treatment with venetoclax.

These findings suggest that venetoclax has the ability to cross the blood-brain barrier and reach therapeutic concentrations in the CSF. The results also highlight the potential role of venetoclax in improving clinical outcomes for patients with CNS complications associated with hematological malignancies. Further investigations can be conducted to explore the utility of venetoclax in treating such complications and potentially enhancing patient outcomes.