Priya Shankarappa, C. Peer, Arman Odabas
Apr 18, 2020
Citations
0
Influential Citations
8
Citations
Quality indicators
Journal
Cancer Chemotherapy and Pharmacology
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. 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: 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, pexidartinib 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 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.