Abstract 1672: The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Abstract

Abstract Background: Sorafenib is an oral multikinase inhibitor that targets intracellular and receptor protein kinases thought to be crucial in the pathogenesis and growth of many tumors including brain tumors. Sorafenib is FDA approved for advanced renal cell and hepatocellular carcinoma. Clinical trials 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: Sorafenib 7.3 mg free base equivalent/kg was administered as a 1h IV infusion in 20% cyclodextrin and normal saline to 3 NHP with IV catheters and Ommaya reservoirs. Serial paired plasma and CSF samples were drawn over 24h for PK analysis. Sorafenib was quantified with a validated liquid chromatography/tandem mass spectrometry assay. The lower limit of quantification for plasma and CSF was 5 ng/mL and 0.025 ng/mL, respectively. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC CSF : AUC plasma. Plasma free drug exposures (AUC) were calculated from published values for human plasma protein binding (99.5%). Results: IV administration of sorafenib was well tolerated in the NHP without evidence of clinical toxicity. The PK parameters of sorafenib in NHP for plasma and CSF are described in the table below. The mean CSF penetration of sorafenib was 0.02%. When corrected for plasma protein binding, the mean CSF penetration was 3.4%. Conclusions: Sorafenib is well tolerated in NHP and measureable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.Plasma and CSF PK of sorafenib in NHPAnimalCmax plasma [µg/mL]Clearance [mL/min/kg]AUC 0-24h plasma [µg•h/mL]Cmax CSF [µg/mL]AUC 0-24h CSF [µg•h/mL]CSF penetration [%]17.62.231.20.000450.00420.01326.42.029.60.000580.00660.02233.41.323.20.000460.00340.015Mean5.81.728.00.000500.00480.02SD2.10.54.30.000070.00160.005 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1672.