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Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients
Armin Sebastian Guntner1, Andreas Peyrl2, Lisa Mayr2
1Institute of Analytical Chemistry, Johannes Kepler University, Linz, Austria.
Abstract:
Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1-10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.
Insights
Small molecule drugs show limited central nervous system (CNS) penetration in pediatric brain tumors. This study measured drug levels in cerebrospinal fluid (CSF), finding some drugs penetrate the blood-brain barrier (BBB), aiding future precision medicine for CNS tumors.
Area of Science:
- Pharmacology
- Oncology
- Neuroscience
Background:
- Precision medicine with small-molecule inhibitors has improved cancer outcomes but faces challenges in treating central nervous system (CNS) tumors.
- Poor blood-brain barrier (BBB) penetration limits the efficacy of these drugs against CNS tumors, with limited data available for CNS-tumor patients.
- Cerebrospinal fluid (CSF) drug penetration serves as a surrogate for CNS penetration, crucial for understanding drug delivery in brain tumor patients.
Purpose of the Study:
- To evaluate the penetration of oral anti-cancer drugs and their metabolites into the cerebrospinal fluid (CSF) of pediatric brain tumor patients.
- To correlate CSF drug concentrations with established predictors of blood-brain barrier (BBB) penetration, including drug properties and in silico models.
- To assess the feasibility of using Ommaya reservoirs for measuring CSF drug concentrations in clinical trials.
Main Methods:
- Analysis of 7 oral anti-cancer drugs and their metabolites in 42 CSF samples from 9 pediatric brain tumor patients using high-performance liquid chromatography-mass spectrometry (HPLC-MS).
- Samples were collected via Ommaya reservoirs.
- Comparison of measured CSF drug concentrations with predictors like ABCB1 substrate character, physicochemical properties, and in silico algorithms.
Main Results:
- High CSF penetration (>10 nM) was observed for ribociclib, vorinostat, and imatinib; moderate penetration (1-10 nM) for regorafenib and dasatinib.
- Panobinostat and nintedanib were not detected in CSF. Active metabolites of imatinib and ribociclib were identified.
- Low molecular weight, high free-drug proportion, and low ABCB1 efflux correlated with BBB penetration, while in silico algorithms showed poor correlation.
Conclusions:
- Measuring CSF drug concentrations via Ommaya reservoirs is feasible and valuable for future clinical trials in CNS tumor patients.
- Certain small-molecule inhibitors and their active metabolites can penetrate the CNS in pediatric brain tumor patients.
- Physicochemical properties and efflux transporter characteristics are key factors influencing CNS penetration, providing guidance for drug development.
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