Cynthia Lester McCully1, Louis T Rodgers1,2, Rafael Cruz1,3, Marvin L Thomas4, Cody J Peer2, William D Figg2, Katherine E Warren1. 1. Pediatric Neuro-Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 2. Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 3. Laboratory Animal Science Program and Leidos Biomedical Research, Inc., National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 4. Office of Research Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
BACKGROUND: Epigenetic modifiers are being investigated for a number of CNS malignancies as tumor-associated mutations such as isocitrate dehydrogenase mutations (IDH1/IDH2) and H3K27M mutations, which result in aberrant signaling, are identified. We evaluated the CNS exposure of the DNA methyltransferase inhibitor, 5-azacytidine (5-AZA), in preclinical nonhuman primate (NHP) models to inform its clinical development for CNS tumors. METHODS: 5-AZA and 5-AZA+Inulin pharmacokinetics (PK) were evaluated in NHPs (n = 10) following systemic (intravenous [IV]) and intrathecal (intraventricular [IT-V], intralumbar [IT-L], and cisternal [IT-C]) administration. Plasma, cerebrospinal fluid (CSF), cortical extracellular fluid (ECF), and tissues were collected. 5-AZA levels were quantified via ultra-high-performance liquid chromatography with tandem mass spectrometric detection assay and inulin via ELISA. PK parameters were calculated using noncompartmental methods. RESULTS: After IV administration, minimal plasma exposure (area under the curve [AUC] range: 2.4-3.2 h*µM) and negligible CSF exposure were noted. CSF exposure was notably higher after IT-V administration (AUCINF 1234.6-5368.4 h*µM) compared to IT-L administration (AUCINF 7.5-19.3 h*µM). CSF clearance after IT administration exceeded the mean inulin CSF flow rate of 0.018 ± 0.003 ml/min as determined by inulin IT-V administration. 5-AZA IT-V administration with inulin increased the 5-AZA CSF duration of exposure by 2.2-fold. IT-C administration yielded no quantifiable 5-AZA ECF concentrations but resulted in quantifiable tissue levels. CONCLUSIONS: IT administration of 5-AZA is necessary to achieve adequate CNS exposure. IT administration results in pronounced and prolonged 5-AZA CSF exposure above the reported IC50 range for IDH-mutated glioma cell lines. Inulin administered with 5-AZA increased the duration of exposure for 5-AZA. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2020.
BACKGROUND: Epigenetic modifiers are being investigated for a number of CNS malignancies as tumor-associated mutations such as isocitrate dehydrogenase mutations (IDH1/IDH2) and H3K27M mutations, which result in aberrant signaling, are identified. We evaluated the CNS exposure of the DNA methyltransferase inhibitor, 5-azacytidine (5-AZA), in preclinical nonhuman primate (NHP) models to inform its clinical development for CNS tumors. METHODS: 5-AZA and 5-AZA+Inulin pharmacokinetics (PK) were evaluated in NHPs (n = 10) following systemic (intravenous [IV]) and intrathecal (intraventricular [IT-V], intralumbar [IT-L], and cisternal [IT-C]) administration. Plasma, cerebrospinal fluid (CSF), cortical extracellular fluid (ECF), and tissues were collected. 5-AZA levels were quantified via ultra-high-performance liquid chromatography with tandem mass spectrometric detection assay and inulin via ELISA. PK parameters were calculated using noncompartmental methods. RESULTS: After IV administration, minimal plasma exposure (area under the curve [AUC] range: 2.4-3.2 h*µM) and negligible CSF exposure were noted. CSF exposure was notably higher after IT-V administration (AUCINF 1234.6-5368.4 h*µM) compared to IT-L administration (AUCINF 7.5-19.3 h*µM). CSF clearance after IT administration exceeded the mean inulin CSF flow rate of 0.018 ± 0.003 ml/min as determined by inulin IT-V administration. 5-AZA IT-V administration with inulin increased the 5-AZA CSF duration of exposure by 2.2-fold. IT-C administration yielded no quantifiable 5-AZA ECF concentrations but resulted in quantifiable tissue levels. CONCLUSIONS: IT administration of 5-AZA is necessary to achieve adequate CNS exposure. IT administration results in pronounced and prolonged 5-AZA CSF exposure above the reported IC50 range for IDH-mutated glioma cell lines. Inulin administered with 5-AZA increased the duration of exposure for 5-AZA. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2020.
Authors: Stephen C Mack; Christopher G Hubert; Tyler E Miller; Michael D Taylor; Jeremy N Rich Journal: Nat Neurosci Date: 2016-01 Impact factor: 24.884
Authors: Cynthia M Lester McCully; John Bacher; Rhonda P MacAllister; Emilie A Steffen-Smith; Kadharbatcha Saleem; Marvin L Thomas; Rafael Cruz; Katherine E Warren Journal: Comp Med Date: 2015-02 Impact factor: 0.982
Authors: Hazel A Rogers; John-Paul Kilday; Cerys Mayne; Jennifer Ward; Martyna Adamowicz-Brice; Ed C Schwalbe; Steven C Clifford; Beth Coyle; Richard G Grundy Journal: Acta Neuropathol Date: 2011-11-23 Impact factor: 17.088
Authors: Cynthia M Lester McCully; Louis T Rodgers; Rafael Cruz Garica; Marvin L Thomas; Cody J Peer; William D Figg; Dennis E Barnard; Katherine E Warren Journal: Comp Med Date: 2020-10-12 Impact factor: 0.982