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The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

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Summary

Purpose Sorafenib is a small molecule inhibitor of multiple signaling kinases thought to contribute to the pathogenesis of many tumors including brain tumors. Clinical trials with sorafenib in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods 7.3 mg/kg of sorafenib free base equivalent solubilized in 20% cyclodextrin was administered IV over 1 h to three adult rhesus monkeys. Serial paired plasma and CSF samples were collected over 24 h. Sorafenib was quantified with a validated HPLC/tandem mass spectrometry assay. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF : AUCplasma. Results Peak plasma concentrations after IV dosing ranged from 3.4 to 7.6 μg/mL. The mean ± standard deviation (SD) area under the plasma concentration from 0 to 24 h was 28 ± 4.3 μg•h/mL, which is comparable to the exposure observed in humans at recommended doses. The mean ± SD clearance was 1.7 ± 0.5 mL/min/kg. The peak CSF concentrations ranged from 0.00045 to 0.00058 μg/mL. The mean ± SD area under the CSF concentration from 0 to 24h was 0.0048 ± 0.0016 μg•h/mL. The mean CSF penetration of sorafenib was 0.02% and 3.4% after correcting for plasma protein binding. Conclusion Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.

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Acknowledgement

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The views expressed do not necessarily represent the views of the National Institutes of Health or the US government.

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  1. Elizabeth Fox & Frank M. Balis

    Present address: Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA

Authors and Affiliations

  1. Pediatric Oncology Branch, Pharmacology and Experimental Therapeutics Section, National Cancer Institute, 10 Center Drive, Building 10-CRC, Bethesda, MD, 20892, USA

    AeRang Kim, Cindy McCully, Rafael Cruz, Diane E. Cole, Elizabeth Fox, Frank M. Balis & Brigitte C. Widemann

  2. Department of Hematology/Oncology, Children’s National Medical Center, 111 Michigan Ave, NW, Washington, DC, 20010, USA

    AeRang Kim

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  1. AeRang Kim
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  2. Cindy McCully
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Correspondence to AeRang Kim.

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Kim, A., McCully, C., Cruz, R. et al. The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates. Invest New Drugs 30, 524–528 (2012). https://doi.org/10.1007/s10637-010-9585-1

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  • DOI: https://doi.org/10.1007/s10637-010-9585-1

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