Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib

Abstract

Purpose-Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model.Methods-Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m 2 ), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pex-idartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods.Results-Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: C max = 16.50 (± 6.67) μg/mL; T max = 5.00 (± 2.58) h; AUC last = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidarti-n ib was either quantifiable (n = 2), with C max values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma T max , or undetected at all time points (n = 2, LLOQ CSF = 5 ng/mL). Conclusion-Pexidartinibwas well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pex-idartinib after single-dose oral administration to NHPs was limited.

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

“…Among these, Pexidartinib and PLX5622 have been the most widely used in rodent model research [ 45 , 57 , 58 ], which has been extended into non-human primates [ 59 ]. Pexidartinib is orally bioavailable, brain-penetrant [ 60 ] and exhibits a favorable tolerability and safety profile in human studies [ 54 , 61 ]. Apart from targeting CSF-1R and c-Kit, Pexidartinib (PLX3397) shows limited cross reactivity with other tyrosine kinases and has 10 ~ 100-fold selectivity for c-Kit and CSF1R over other related kinases, including PDGFRα and FLT3 [ 62 , 63 ].…”

The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke)

“…Altogether, resistance to CSF-1R monotherapy may be explained by the cellular heterogeneity of the tumor microenvironment beyond GAMM. Accordingly, single-agent therapy with CSF-1R inhibitor has demonstrated very modest results in glioblastoma clinical trials, showing no significant improvement of the progression-free survival of the patients ( 79 , 80 ).…”

Eco-Friendly, Simple, Fast, and Sensitive UPLC-MS/MS Method for Determination of Pexidartinib in Plasma and Its Application to Metabolic Stability

“…Few studies have been recently published for the quantitative determination of PX in pharmaceutical products using HPLC [ 16 ], in plasma to study PX population pharmacokinetics [ 17 ] and pediatric pharmacokinetics/ pharmacodynamics [ 15 ], in cerebrospinal fluids to measure its brain uptake [ 18 ] and in drug-drug interaction, studies using LC-MS/MS [ 11 ]. However, these studies lack the details of the methods chromatographic parameters and extraction techniques.…”