scholarly journals Cellular immune surveillance of central nervous system bypasses blood-brain barrier and blood-cerebrospinal-fluid barrier: Revealed with the New Marburg cerebrospinal-fluid model in healthy humans

2015 ◽  
Vol 87 (3) ◽  
pp. 227-243 ◽  
Author(s):  
Tilmann O. Kleine
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Fluid Model ◽  
Immune Surveillance ◽  
Brain Barrier ◽  
Healthy Humans ◽  
Blood Brain ◽  
Cellular Immune

scholarly journals Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic Analysis of the Cerebrospinal Fluid in Pediatric Leukemia Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Ahmed Hamed Salem ◽  
Mohamed A Badawi ◽  
Andrew E. Place ◽  
Tammy L. Palenski ◽  
Richard Arrendale ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Plasma Concentrations ◽  
Central Nervous System Involvement ◽  
Lymphocytic Leukemia ◽  
Brain Barrier ◽  
Publicly Traded ◽  
Blood Brain

Introduction: Venetoclax is a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults and is currently being evaluated in several hematologic and solid malignancies. While plasma pharmacokinetics (PK) of venetoclax is well documented, data regarding the accumulation of venetoclax into the central nervous system (CNS) are limited. Venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the blood brain barrier (BBB). Moreover, venetoclax is a substrate of the P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS. In this analysis we characterized the passage of venetoclax into the CNS using PK samples collected during a phase 1 study (NCT03236857) of pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy. Methods: PK samples from cerebrospinal fluid (CSF) were collected at screening and if a lumbar puncture was performed as standard of care during treatment. Plasma PK samples were collected throughout the study. CSF and plasma concentrations of venetoclax were determined using liquid-liquid extraction followed by liquid chromatography (LC) with tandem mass spectrometric detection (MS/MS). The lower limit of quantitation for venetoclax was 2.14 ng/mL in plasma and 0.1ng/mL in CSF. Results: There was a total of 66 samples from 33 patients with relapsed or refractory AML or ALL. The venetoclax concentration in CSF ranged between <0.1 and 13 ng/mL with a mean concentration of 3 ng/mL. Of the 66 CSF samples collected, 17 CSF samples (from 9 patients) had a plasma PK sample collected on the same day. The venetoclax CSF concentrations in this subgroup were consistent with the overall group and ranged between <0.1 and 11 ng/mL with a mean concentration of 2.8 ng/mL. Venetoclax plasma concentrations ranged from <2 ng/mL to 4.3 ug/mL. The mean plasma-to-CSF ratio was 300 with a range of 67-1003. This mean is more than 4-fold higher than the blood-to-brain ratio observed preclinically in mice. The plasma-to-CSF ratios did not show a trend over the dosing interval. Conclusion: To our knowledge this is the first study reporting venetoclax CSF pharmacokinetics in the AML and ALL setting. The lower disposition observed in humans is contrary to our expectation, given the significantly higher expression of P-gp in mice BBB compared to humans and suggests that other factors are involved in venetoclax disposition to the CSF. The ability of venetoclax to cross the blood brain barrier may explain the reported activity of venetoclax in treatment of hematologic malignancies with CNS involvement1,2. References: Reda G, Cassin R, Dovrtelova G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104(5):e222-e223. doi:10.3324/haematol.2018.213157 Beziat G, Gauthier M, Protin C, et al. Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep. 2020;8(2):269-273. Published 2020 Jan 10. doi:10.1002/ccr3.2580 Disclosures Salem: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Place:Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Arrendale:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

scholarly journals Central nervous system delivery of molecules across the blood-brain barrier

2021 ◽  
pp. 104952
Author(s):  
Fabien Gosselet ◽  
Rodrigo Azevedo Loiola ◽  
Anna Roig ◽  
Anna Rosell ◽  
Maxime Culot
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain
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