PHRM-03. CEREBROSPINAL FLUID PENETRATION OF PEXIDARTINIB (PLX3397), A CSF1R INHIBITOR, IN A NONHUMAN PRIMATE MODEL. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Odabas, Arman; McCully, Cynthia M Lester; Cruz, Rafael; Figg, William D; Glod, John; Rymar, Andrey; Peer, Cody; Warren, Katherine E
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i157
• 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/noy059.581
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Pexidartinib (PLX3397) is a colony stimulating factor-1 receptor (CSF1R) inhibitor under clinical evaluation including potential CNS tumor treatment. This study aims to estimate CNS penetration of pexidartinib in a nonhuman primate (NHP) CSF Reservoir model. METHODS: 4 male rhesus macaques, each with an indwelling CSF ventricular reservoir and central venous lines, were used. NHPs received pexidartinib (40 mg/kg, single dose, human equivalent dose of 20 mg/m 2 ) administered orally. Serial paired samples of blood and CSF were collected from 0-8, 24, 48, and 72 hours. Pexidartinib concentrations were assayed by Plexxikon Inc. using HPLC/MS/MS. Pharmacokinetic analysis was performed with Phoenix ® WinNonlin ® software. RESULTS: Average plasma pharmacokinetic parameters were as follows: Cmax = 16500 (± 6700) ng/mL; Tmax = 5 (± 2.57) hours; AUCD→∞ = 262156 (± 105424) hr*ng/mL; CL = .178 (± .088) L/hr/kg. Pexidartinib in the CSF was not detected (n=2, LLOQCSF = 5 ng/ml) or was quantifiable (n=2) with Cmax of 16.1 and 10.1 ng/ml. CSF values were lower than predicted based on steady-state rat data which showed CSF:plasma between .0015 and .0044. Plasma protein binding of pexidartinib exceeds 99% in equilibrium dialysis experiments, which is consistent with low CSF:plasma. CONCLUSIONS: CSF penetration of pexidartinib after oral administration in a NHP was limited and lower than predicted by a rodent steady-state model. Pexidartinib is well-tolerated in rhesus macaques. FUTURE WORK: Subsequent studies will examine pharmacokinetics of pexidartinib in plasma and CSF at steady state, and investigate intrathecal administration of pexidartinib. ACKNOWLEDGMENTS: PLX3397 was supplied by Plexxikon Inc.