PHRM-01. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE DNA HYPOMETHYLATING AGENT, GUADECITABINE (SGI-110), FOLLOWING SUBCUTANEOUS ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Lester McCully, Cynthia M; Odabs, Arman; Cruz, Rafael; Peer, Cody; Figg, William D; Glod, John W; Warren, Katherine E
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i156
• Page End: i157
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.579
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Guadecitabine, a potent hypomethylating agent currently being studied in clinical trials, is a dinucleotide that is resistant to degradation by cytidine deaminase resulting in an extended release of the active metabolite decitabine following subcutaneous (SC) administration. The CSF exposure of Guadecitabine following SC administration was evaluated via plasma and CSF pharmacokinetics (PK) in a nonhuman primate CSF Ventricular Reservoir or Lumbar Port model, which permits humane, rapid, serial CSF collection. METHODS: Guadecitabine (2.3 mg/kg, Human Equivalent Dose 45 mg/m 2 ) was administered to 4 rhesus macaques subcutaneously x 5 days. Following administration, multiple serial paired plasma and CSF samples were collected for 0-24 hours on day 1, prior to dosing on days 2-5, and at day 6 (24 hours post the final dose). Guadecitabine's active metabolite, decitabine, was quantified via an LC-MS/MS assay and PK parameters calculated using noncompartmental methods. RESULTS: Mean peak plasma PK results were: Cmax 44.98 ng/ml ± 13.9; Tmax 0.75 hr ± 0.29, Half-Life 1.3 hr ± 0.41, AUC0-∞ 135.22 hr*ng/ml ± 32.9, and Clearance 381.60 L/hr/m2 ± 137.7. Guadecitabine CSF concentrations were detectable, but below the level of quantification (n=2) or undetectable (n=2). All macaques experienced a mild to moderate lymphocytopenia, but otherwise tolerated guadectabine. Lymphopenia resolved within 30 days. CONCLUSIONS: Systemic delivery of Guadecitabine does not provide adequate CSF exposure of decitabine when administered subcutaneously. The agent was well tolerated in the NHP. FUTURE STUDIES: Continuing studies will examine the PK and tolerability of the drug following intraventricular administration in this nonhuman primate model.