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

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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.

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References

  1. Warren KE (2018) Beyond the blood: brain barrier: the importance of central nervous system (CNS) pharmacokinetics for the treatment of CNS tumors, including diffuse intrinsic pontine glioma. Front Oncol 8:239

    Article  Google Scholar 

  2. Sarkaria JN et al (2018) Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol 20(2):184–191

    Article  CAS  Google Scholar 

  3. Fernandes G et al (2019) Recent advances in the discovery of small molecules targeting glioblastoma. Eur J Med Chem 164:8–26

    Article  CAS  Google Scholar 

  4. Gallitto M et al (2019) Role of radiation therapy in the management of diffuse intrinsic pontine glioma: a systematic review. Adv Radiat Oncol 4(3):520–531

    Article  Google Scholar 

  5. Butowski N et al (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy foundation early phase clinical trials Consortium phase II study. Neuro Oncol 18(4):557–564

    Article  Google Scholar 

  6. Mantovani A et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  CAS  Google Scholar 

  7. Binnewies M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–550

    Article  CAS  Google Scholar 

  8. Nowicki A et al (1996) Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer 65(1):112–119

    Article  CAS  Google Scholar 

  9. Tap WD et al (2015) Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med 373(5):428–437

    Article  CAS  Google Scholar 

  10. Coniglio SJ et al (2012) Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med 18:519–527

    Article  CAS  Google Scholar 

  11. Prada CE et al (2013) Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol 125(1):159–168

    Article  CAS  Google Scholar 

  12. Patwardhan PP et al (2014) Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res 20(12):3146–3158

    Article  CAS  Google Scholar 

  13. Lester McCully CM et al (2015) Development of a cerebrospinal fluid lateral reservoir model in rhesus monkeys (Macaca mulatta). Comp Med 65(1):77–82

    PubMed  PubMed Central  Google Scholar 

  14. Baratz EMC, Shih J et al (2018) Comparison of pharmacokinetic paramters between non-human primates and human patients. In ISPNO. 2018: Denver

  15. Guide for the Care and Use of Laboratory Animals, I.f.L.A. Research, Editor (2011) National Academy of Sciences: National Research Council

  16. Lee JH et al (2020) A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors. Invest New Drugs 38(1):99–110

    Article  CAS  Google Scholar 

  17. Yan D et al (2017) Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene 36(43):6049–6058

    Article  CAS  Google Scholar 

  18. Redzic Z (2011) Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8(1):3

    Article  Google Scholar 

  19. Morris ME, Rodriguez-Cruz V, Felmlee MA (2017) SLC and ABC transporters: expression, localization, and species differences at the blood-brain and the blood-cerebrospinal fluid barriers. AAPS J 19(5):1317–1331

    Article  Google Scholar 

  20. Ito K et al (2011) Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. J Pharm Sci 100(9):3939–3950

    Article  CAS  Google Scholar 

Download references

Funding

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, Grant ZIA BC 011340. PLX3397 was graciously supplied by Plexxikon Inc. The work was performed by intramuralNIH employees under project ZIC SC 006537

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Authors and Affiliations

  1. Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA

    Priya S. Shankarappa, Cody J. Peer, Arman Odabas & William D. Figg

  2. Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA

    Priya S. Shankarappa, Arman Odabas, Cynthia L. McCully, Rafael C. Garcia & Katherine E. Warren

  3. Laboratory Animal Science Program, Leidos Biomedical Research Inc, NIH, Bethesda, MD, USA

    Rafael C. Garcia

  4. Dana Farber Cancer Institute, 450 Brookline Avenue, DANA 3154, Boston, MA, 02215, USA

    Katherine E. Warren

Authors
  1. Priya S. Shankarappa
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  2. Cody J. Peer
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  3. Arman Odabas
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  4. Cynthia L. McCully
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  5. Rafael C. Garcia
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  6. William D. Figg
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  7. Katherine E. Warren
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Correspondence to Katherine E. Warren.

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Shankarappa, P.S., Peer, C.J., Odabas, A. et al. Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib. Cancer Chemother Pharmacol 85, 1003–1007 (2020). https://doi.org/10.1007/s00280-020-04071-7

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  • DOI: https://doi.org/10.1007/s00280-020-04071-7

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