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. 2020 May;85(5):1003-1007.
doi: 10.1007/s00280-020-04071-7. Epub 2020 Apr 18.

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

Priya S Shankarappa  1   2 , Cody J Peer  1 , Arman Odabas  1   2 , Cynthia L McCully  2 , Rafael C Garcia  2   3 , William D Figg  1 , Katherine E Warren  4   5
Affiliations

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

Priya S Shankarappa et al. Cancer Chemother Pharmacol. 2020 May.

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/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pexidartinib 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: Cmax = 16.50 (± 6.67) μg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL).

Conclusion: Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited.

Keywords: Brain tumor; Central nervous system; Glioma; Macrophage; Pharmacokinetics; Tyrosine kinase inhibitor.

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Conflict of interest statement

Conflict of interest The authors declare they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Locations of CSF ventricular reservoirs in the NHPs studied
See this image and copyright information in PMC

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