Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib
Autor: | Cody J. Peer, William D. Figg, Priya Shankarappa, Cynthia McCully, Rafael C. Garcia, Arman Odabas, Katherine E. Warren |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Cmax Aminopyridines Biological Availability Antineoplastic Agents Receptor Macrophage Colony-Stimulating Factor Pharmacology Toxicology Article Colony stimulating factor 1 receptor 03 medical and health sciences 0302 clinical medicine Cerebrospinal fluid Pharmacokinetics Oral administration Glioma medicine Animals Pyrroles Pharmacology (medical) Receptor Dose-Response Relationship Drug Brain Neoplasms business.industry Protein-Tyrosine Kinases medicine.disease Macaca mulatta 030104 developmental biology Oncology Blood-Brain Barrier 030220 oncology & carcinogenesis Cerebrospinal fluid penetration Drug Monitoring business |
Zdroj: | Cancer Chemother Pharmacol |
ISSN: | 1432-0843 0344-5704 |
DOI: | 10.1007/s00280-020-04071-7 |
Popis: | 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: Pexidartinib was 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. |
Databáze: | OpenAIRE |
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