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/m2) 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.