Abstract 7163: Pharmacokinetics assessment of intranasal NEO100 treatment on blood-brain barrier disruption and brain penetration of drugs in rodent brain

Abstract

Abstract Background: Insufficient drug concentrations reaching the brain-localized tumor tissue remains one of the major challenges in the treatment of glioblastoma (GBM). An intranasal (IN) formulation of NEO100 (NeOnc Technologies, Inc., Los Angeles), a highly purified version of perillyl alcohol, has been recently reported to enhance drug concentrations in the brain upon IN co-delivery. Here, we report detailed pharmacokinetics (PK) and tissue analysis to quantitatively examine the extent of increase in drug concentrations in the brain after IN NEO100 administration. Furthermore, we also confirmed that IN NEO100 increases brain drug concentration by circumventing the blood brain barrier. Method: For PK analysis, either IN or oral formulation of a three-drug cocktail (ZEI, consisting of ZN-c3, everolimus, and infigratinib) was used to evaluate the impact of 3% IN NEO100 on the brain penetration profile of the three individual drugs. Athymic mice were grouped into four cohorts to receive 1) oral ZEI; 2) IN ZEI; 3) oral ZEI with IN NEO100; and 4) IN ZEI with IN NEO100. At 2, 4 and 6 hours post ZEI dosing, drug levels in plasma and brain tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). For BBB disruption study, athymic mice were treated with IN delivery of saline (negative control) or 3% NEO100 one hour post intravenous Evans blue (2%) administration. Tumor bearing mice with disrupted BBB served as positive control. Two hours post Evans blue administration, animals were perfused, and brains were collected and sectioned for confocal microscopy to image Evan’s blue autofluorescence. Results: PK analysis revealed that brain-to-plasma ratios (Kp) for ZN-c3, everolimus, and infigratinib remained nearly equal, independent of the route of administration, i.e. 0.11, 0.03, and 0.82 vs 0.09, 0.03, and 0.87, for IN vs oral routes, respectively. Administration of the ZEI together with IN NEO100, either through oral or IN routes, resulted in higher drug concentrations, both in the plasma and in the brain. However, while overall drug exposure was increased, Kp values of the drugs were not changed. Confocal imaging of brains from mice treated with 3% IN NEO100 did not show presence of Evans blue autofluorescence while positive control mice with disrupted BBB within the tumor core displayed high Evans blue fluorescence. Conclusions: Co-administration of IN NEO100 with ZN-c3, everolimus, and infigratinib increases their brain and plasma exposure. As a result, no significant increase in brain-to-plasma partition was registered for any of the three drugs tested in this study. IN NEO100-mediated increase in brain drug concentration was independent of BBB disruption Citation Format: Anil Thaghalli Shivanna, Tigran Margaryan, Mariya Stavnichuk, William Knight, Sonam Patel, Elaine Cabrales, An-Chi Tien, Thomas Chen, Nader Sanai, Artak Tovmasyan, Shwetal Mehta. Pharmacokinetics assessment of intranasal NEO100 treatment on blood-brain barrier disruption and brain penetration of drugs in rodent brain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7163.